Iodinated 3-aminobenzamides

ABSTRACT

3-Amino-2,4,6-triiodobenzoic acids optionally substituted in the 5-position by amino or carboxy or a derivative thereof react with dibasic acid anhydrides to give the corresponding cyclic imides (A), which can be hydrolyzed to the corresponding anilic acids (B). The latter can be further alkylated on the anilide nitrogen atom. Compounds A and B are useful as cholecystographic and urographic agents.

United States Patent Ackerman [451 May 30, 1972 [5 IODINATEDS-AMINOBENZANIIDES References Ciwd [72] Inventor: James H. Ackerman,Bethlehem, N.Y. UNITED STATES PATENTS Assignee= Sterling g New rk, NY.3,446,837 5/1969 Wallingford ..260/558 [22] Filed: Apr. 2,1970 fl 21Appl. No.: 25,262 P' R-Jiles Assistant ExaminerHarry 1. Moatz RelatedUS. Application Data Attorney-Elmer J. Lawson, B. Woodrow Wyatt, ThomasL. [63] Continuation-impart of S81. No. 808,653, Mar. 19, mm Webb and1969, Pat. No. 3,609,147, and a continuation-in-part W of Ser. No.715,583, Mar. 25, 1968, abandoned, Ser. No. 808,653 is acontinuation-in-part of Ser. No. 57 BSTR T 715,558, Mar. 25, 1968,abandoned, which is a continuafiomimpart of 550 614, May 17, 1966,S-AIIIiIIO'ZAfi-IUIOdObCHZOIC acids optionally substituted in abandonedthe 5-position by amino or carboxy or a derivative thereof react withdibasic acid anhydrides to give the corresponding 52 U.S. Cl ..260/247.2A, 260/243 B, 260/247.2 R cyclic imides (A), which can be "Ydmlyzed 2 77 260/29177 260/326'3 260/326'5: ing anilic acids (B). The latter can befurther alkylated on the 260/470, 260/471 R, 260/471 A, 260/516, 260/513anilide nitrogen atom. Componnds A and B are useful as R, 260/518 A,260/519, 260/557 R, 260/578 holecystogra hic and urographlc agents.

260/518 A, 424/5 51 Int. Cl ..C07c 103/28 58 Field of Search ..260/558,294, 326.85, 247.2, 3 Claims, No Drawings This application is acontinuation-in-part of my prior copending application, Ser. No.808,653, filed Mar. 19, 1969, now U.S. Pat. No. 3,609,147, which is inturn a continuationin-part of my prior application, Ser. No. 7l5,558,filed Mar. 25, 1968, now abandoned, which is in turn acontinuation-inpart of my application, Ser. No. 550,614, filed May 17,1966, now abandoned. This application is also a continuation-in-part ofmy prior application, Ser. No. 715,583, filed Mar. 25, 1968, nowabandoned.

This invention relates to iodinated aniline derivatives and theirpreparation, and more particularly is concerned with iodinated benzenecyclic imide derivatives and the corresponding anilic acids, withintermediates therefor, and with methods for their preparation.

A preferred aspect of the invention resides in compounds of theformulas:

wherein Y is lower-alkylene group wherein two or three carbon atomsseparate the carbonyl groups, vinylene, or a 1,3- propylene groupwherein the two-carbon atom is replaced by O, S, S or SO. Y" is a singlebond, vinylene, or an alkylene bridge having from one to eight carbonatoms or such a group interrupted by from one to three members selectedfrom O, S, SO and S0 said members, when more than one, being separatedby at least two carbon atoms; Z is OH, O-lower-alkyl, lower-alkyl,phenyl, NH NH(lower-alkyl), N(lower-alkyl) morpholino, pyrrolidino orpiperidino; R is H, H N, Z- CO,

HOOCY'CONH, HOOCY'CON(lower-alkyl), TCONH, TCONHCH or(TCO)N(lower-alkyl), where T is hydrogen, cycloalkyl of three to sixring members, or alkyl of one to eight carbon atoms optionallyinterrupted by from one to four oxygen atoms, each oxygen, when morethan one, being separated by at least two carbon atoms; R is hydrogen,lower-alkyl, hydroxy-lower-alkyl, lower-alkoxylower-alkyl, orlower-a1koxy-lower-alkoxy-lower-alkyl, except that in formula (B) atleast one of R and R' is other than hydrogen; and R" is hydrogen orlower-alkyl.

In the above formulas (A) and (B), Y stands, inter alia, for alower-alkylene group wherein two or three carbon atoms separate thecarbonyl groups and thus can be an ethylene or propylene groupoptionally substituted by lower-alkyl. The group Y can have from two tosix carbon atoms and includes and the like. Y also stands for a Z-oxaorZ-thial ,3-propylene group having from two to four carbon atoms, forexample,

R" stands for lower-alkyl, the lower-alkyl and lower-alkoxy groups havefrom one to six carbon atoms, thus including, for example, methyl,methoxy, ethyl, ethoxy, propyl, isopropyl, butyl, butyloxy, isobutyl,pentyl', hexyl and hexyloxy.

1n the foregoing definitions, where T stands for cycloalkyl of three tosix ring members, the cycloalkyl thus includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and loweralkylated derivatives thereof, forexample, 2-methylcyclopropyl, 3-ethylcyclopentyl,3,4-dimethylcyclohcxyl, and the like.

The method of preparation of the compounds offormulus A and B variesaccording to the structure desired as follows: 1. Compounds of formula Awhere R is H, Z-CO,

a. Using a dibasic acid anhydride:

A compound of the formula R --NHQ wherein R is H, Z-CO,

HOOCYCON(lower-alkyl), T-CO-NH, TCO- NHCH- or (TCO)N(lower-alkyl), Z, Tand Y having the same meanings given hereinabove, and Q is hydrogen orlower-alkanoyl, is heated with an acid anhydride of the formula C O Y NWhen Y is a lower-alkylene groups, the reaction is preferably carriedout in the presence of a strong acid catalyst, for example, sulfuricacid or phosphoric acid. When the reaction is carried out with acompound of formula C wherein Q is lower-a1- kanoyl, the lower-alkanoylgroup is lost and replaced by the cyclic imide group. i

b. Using a succinyl or glutaryl chloride:

A compound of formula C where Q is hydrogen is heated with a compound ofthe formula ClOC-YCOCI, where Y is a lower-alkylene group wherein two orthree carbon atoms separate the carbonyl groups, in an inert solvent.

2. Compounds of formula B where R is hydrogen.

a. Where Y is within the scope of Y, and R" is hydrogen:

These compounds can be prepared by alkaline hydrolysis of thecorresponding compounds of formula A. The reaction takes place inaqueous solution under mild conditions, at room temperature.

b. Where R is as given under method 1 above:

These compounds can be prepared by reacting a compound of formula Cwhere Q is hydrogen with a half ester half acid chloride, Cl-COY'COOR,in an inert solvent, affording a compound of formula B where R islower-alkyl. Hydrolysis of the latter under mild alkaline conditionsgives an anilic acid of formula B where R" is hydrogen.

3. Compounds of fonnulas A and B wherein R is NH, or T-- CO-NH.

These compounds can be prepared from 3-amino-5-nitrobenzoic acid or anester or amide thereof according to the following flow sheet (2 and Yhaving the meanings given hereinabove):

3 Amino-5-nitrobenzoic acid or an amide or ester thereof is reacted withan anhydride, O( CO) Y, to give the cyclic imide (D). The latter caneither be hydrogenated under acid or neutral conditions to give theamino cyclic imide (E) or hydrolyzed under basic conditions to give thecorresponding nitro-anilic acid (F). The nitro-anilic acid in turn canbe hydrogenated to the amino-anilic acid (G). Iodination of the aminocyclic imide (E) atoms a compound of formula A where R is H N, andiodination of the amino-anilic acid (G) gives a compound of formula Bwhere R is H N and R is H. The primary amino groups can then, ifdesired, be acylated with an acid anhydride or acid chloride to give,respectively, a compound of formula A where R is T-CO-NH, or a compoundof formula B where R is T-CONH and R is hydrogen. 4. Compounds offormulas A and B where the groups in the 3- and S-positions areidentical.

These are most conveniently prepared from 3,5-diamino-2,4,6-triiodobenzoic acid, or an ester or amide thereof. The

latter is reacted with at least two equivalents of an anhydride, O(CO)Y, to afford a compound of formula A where R is Y(C) N, which then canbe hydrolyzed to a compound of fonnula B where R is HOOC-Y-CONH and R isH. The 5 starting material can also consist of a 3-lower-alkanoylamino-5-amino-2,4,6-triiodobenzoic acid or a 3,5-bis(lower-alkanoylamino)benzoic acid. In the reaction with the anhydride the lower-alkanoylgroups are replaced by cyclic imide groups. Alternatively, a methodanalogous to method 2( b) above can be used, for example, reacting3,5-diamino-2,4,6- triiodobenzoic acid with a half ester half acidchloride Cl- CO-YCOOR", afiording a compound of formula 8 where R isR"OCOYCONH, R is H and R" is lower-alkyl. 5. Compounds of fonnula Bwherein R is lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkylor lower-alkoxylower-alkoxy-lower-alkyl.

These compounds can be prepared by N-alkylation of the correspondingcompounds where R is hydrogen. The alkylation is effected by the actionof R' halide, R sulfate, R alkylsulfonate or R arylsulfonate in thepresence of aqueous alkali, wherein R is lower-alkyl,hydroxy-lower-alkyl, lower-alkoxylower-alkyl orlower-alkoxy-lower-alkoxy-loWer-alkyl. If the starting material is acompound of formula B where R is T CO-NH or HOOCY'CONH, alkylationoccurs on both nitrogens simultaneously.

6. Compounds of formulas A and B wherein R is (T CO )N( lower-alkyl Analternative synthesis of these compounds is outlined in the followingflow sheet:

HzN N02 TCOCl v T-CONH NO2 (IJOZ 12 TCONH NH2 co-z I I m T--CONH NH2(lower-alkylhsol CO-Z I I I I A B T-CON -NH-.

1 lower- I alkyl In the foregoing formulas T and 2 have the meaningsgiven hereinabove. 3-Amino-5-nitrobenzoic acid or a derivative thereofis treated with an acid chloride, T-COCl, to yield 3 nitro amide (G')which is catalytically reduced to an amino amide (H). The latter isiodinated to give a 2,4,6-triiodo-3- amino-S-acyl-amidobenzoic acid orderivative thereof (J) and rule.

finally alkylated on the amide nitrogen to produce a compound of formulaC where R is (TCO)N(lower-alkyl). The latter can be converted tocompounds of formulas A and B by the methods previously described.

The compounds of the invention of fonnulas A and B where Y and/or Y arealkylene groups interrupted by S0 or SO, can alternatively be preparedby oxidation of the corresponding sulfide -S) compounds with a peracid.The oxidation takes place at room temperature in an inert organicsolvent.

The key reaction in the foregoing methods for preparing the compounds ofthe invention is the formation of the cyclic imide from the substitutedaniline. Prior art methods for the preparation of N-aryl cyclic imidescomprise the formation of the N-aryl-anilic acid followed bycyclodehydration of the latter to form the N-aryl cyclic imide. Thepresent invention provides a process for preparing N-aryl cyclic imidesfrom substituted anilines in a single step.

A process aspect of the invention thus resides in a process forpreparing compounds of the formula (JO-Z R N Y wherein R is H, Z-CO,

R." -N l I Q,

wherein R is H, H N, Z-CO,

T-CO-NH, TCONHCH (TCO)N(lower-alkyl), HOOCYCON(lower-alkyl) or O N (Zand T having the meanings given above); Y is vinylene, a lowenalkylenegroup wherein two or three carbon atoms separate the carbonyl groups, ora l,3-propylene group wherein the two-carbon atom is replaced by O, S,S0 or $0 Q is hydrogen or loweralkanoyl; and X is H or I, X being H whenR is O N, with a compound of the formula a strong acid catalystpreferably being used where Y is loweralkylene. An equimolar quantity oran excess of the anhydride reactant is used, and the reactants areheated together at a temperature between about 50 and 150 C.

If desired, the cyclic imide of formula (K) can be hydrolyzed to thecorresponding anilic acid of formula (Jo--Z and the latter, if desired,where X is iodine, can be N-alkylated with R halide, R sulfate, Ralkylsulfonate or R arylsulfonate, to give a compound of formula 13wherein R is loweralkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkylor loweralkoxy-lower-alkoxy-lower-alkyl.

The structures of the compounds of the invention were determined by themodes of synthesis, by elementary analysis and by neutral equivalentdeterminations. The course of the reactions was followed by thin-layerchromatography.

Those compounds of the invention which are carboxylic acids, can beobtained in the form of salts derived from inorganic bases or organicamines. The compounds of formulaB where R" is hydrogen and Z is OH,being dibasic acids, can form monoor di-salts. Preferred salts are thosewhich are pharmaceutically acceptable, for example, the sodium,magnesium, calcium and N-methylglucamine salts; although all salts areuseful either as characterizing derivatives or as intermediates in thepurification of the acids. The salt forms of the compounds of theinvention are considered the full equivalents of the free acids claimedherein, and thus are part of the same inventive concept.

The compounds of the invention in the form of water-soluble,pharmaceutically acceptable salts are useful as intravenous X-raycontrast media either for visualization of the kidneys and urinary tract(urography) or of the gallbladder (cholecystography). The compounds oflower molecular weight, having from 1 l to about 15 carbon atoms, areprimari ly urographic agents, whereas those of higher molecular weightand greater lipophilic character are primarily cholecystographic agents.The compounds have a low toxicity, intravenous LD values ranging up to20,000 mgJkg. in mice.

The actual quantitative determination of toxicity and radiopaqueeffectiveness for a particular compound is readily detennined bystandard test procedures by technicians trained in pharmacological testprocedures, without the need for any extensive experimentation; Hoppe,J. Am. Pharmaceut. Assn. 48, 368 79 l959); and Hoppe et al., Am. J.Roentgen. Rad. Therap. Nuc. Med. 69, 620-7 l953).

The compounds of the invention were tested for their intravenousurographic or cholecystographic efficacy by standard procedure asfollows: The test compound was injected intravenously in the form of anaqueous solution of the sodium or N-methylglucamine salt to the testanimals, usually cats or rabbits. Each animal was X-rayed at hourlyintervals and the roentgenograms examined and evaluated. The density ofthe organ shadows was interpreted in accordance with a numerical scoringplan designated as the cholecystographic lndex (Cl) or Urographic lndex(Ul), a measure of the efficiency of the test compound, viz.: 0 (none),1 (poor), 2 (fair), 3 (good), 4 (excellent). At a dose level of mg./kg.,the compounds of the invention having cholecystographic propertiesproduced gallbladder shadows having a maximum Cholecystographic lndex of3.0-4.0.

The compounds of the invention are prepared for use by dissolving aphannaceutically acceptable salt form in sterile aqueous medium suitablefor intravenous injection.

The following examples will further illustrate the invention without thelatter being limited thereby.

EXAMPLE l 3-Glutarimido-5-( N-methylacetamido )-2,4,6-triiodobenzoicAcid [A; R is CH CON(CH Y is CH CH CH Z is OH].

A mixture of 117.2 g. of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid and 182 g. of glutaric anhydride was heatedwith stirring on a steam bath. Concentrated sulfuric acid (10 ml. wasadded, and heating and stirring; were continued for 7 hours. Thereaction mixture was added to 700 ml. of water, and the solid productwas collected by filtration and recrystallized from acetic acid. Theresulting 3-glutarimido-5- (N-methylacetamido)-2,4,6-triiodobenzoic acidwas converted to its sodium salt form as follows: the free acid wasslurried with 40 ml. of methanol and a 1N solution of sodium hydroxidein methanol was added with trituration until the solid had dissolved.The sodium salt was precipitated out with ether, and the resulting gunwas triturated with ether and dissolved in methanol. The latter solutionwas decolorized with activated charcoal and the product reprecipitatedwith ether. The product was dissolved in water and the solution filteredand concentrated in vacuo. The residue was dried in vacuo to give thesodium salt of 3 -glutarimido-S-( N-methylacetamido)-2,4,6-triiodobenzoic acid as a pale pink solid, m.p.200-204 C. (dec.).

When the glutaric anhydride in the foregoing preparation was replaced byglutaryl chloride in dioxane solution there was obtained a product inwhich 3-glutarimido-5-(N- methylacetamido)-2,4,6-triiodobenzoic acidcould be identified by thin layer chromatography.

By replacing the 3-amino-5-(N-methylacetamido)-2,4,6- triiodobenzoicacid in the foregoing preparation by a molar equivalent amount of3-amino-5-( N-butylacetamido)-2,4,6- triiodobenzoic acid,3-amino-5-(N-methylpropionamido)- 2,4,6-triiodobenzoic acid, 3-amino-5-(N-methylcaproylamino)-2,4,6-triiodobenzoic acid, 3-amino-5-(N,N-dimethylcarbamoyl)-2,4,6-triiodobenzoic acid, or 3-amino-5-N-methyl-2-methoxyacetamido )-2,4,6-triiodobenzoic acid, there can beobtained, respectively,3-glutan'mido-5-(N-butylacetamido)-2,4,6-triiodobenzic acid [A; R is CHC0n(C H Y is CH CH CH Z is OH], 3-glutarimido-5-(N-methylpropionamido)-2,4,6-triiodobenzoic acid [A; R is CH CH CON(CH Yis CH CH CH Z is OH], 3-glutarimido-5-( N-methylcaproylamino)-2,4,6-triiodobenzoic acid [A; R is CH -,(CH ),,CON(CH Y is CH CH CH Zis OH 1, 3-glutarimido-5-( N,N-dimethylcarbamoyl )-2,4,6- triiodobenzoicacid [A; R is (CH NCO, Y is CH CH CH Z is OH], or 3-glutarimido-5-(N-methyl-2-methoxyacetamido)- 2,4,6-triiodobenzoic acid [A; R is CH OCHCON(CH Y is CH CH CH, Z is 01-1].

By replacing the glutaric anhydride in the foregoing preparation by amolar equivalent amount of 2,3-dimethylsuccinic anhydride,2,3,4-trimethylglutaric anhydride, or 2- methylglutaric anhydride, therecan be obtained, respectively, 3-( 2,3-dimethylsuccinimido )-5-(N-methylacetamido)-2,4,6- triiodobenzoic acid [A; R is CH CON(CH Y CH(CH)CH( CH 3-( 2,3,4 trimethylglutarimido)- 2,4,6-triiodobenzoic acid [A; Ris CH CON(CH Y is CH(CH )CH(CH Z is OH], or3-(2-methylglutarimido)-2,4,6-triiodobenzoic acid [A; R is CH CON(CH Yis CH(CH )CH CH Z is OH].

EXAMPLE 2 3-Succinimido-5-( N-methylacetamido )-2,4,6-triiodobenzoicAcid [A; R is CH CON(CH Y is CH CH Z is OH] was prepared from 87.9 g. of3-amino-5-(N-methylacetamido) 2,4,6-triiodobenzoic acid, 120 g. ofsuccinic anhydride and 6 ml. of sulfuric acid according to the procedureof Example 1, except that a reaction temperature of 130l40 C. was used.The reaction was essentially complete after 30 minutes heating time. Thecompound was isolated in the form of its sodium salt, pale yellow solid,m.p. 220222 C.(dec.

EXAMPLE 3 3-( B-Methylglutarimido )-5-( N-methylacetamido2,4,6triiodo-benzoic Acid [A; R is CH CON(CH Y is CH CH(CH CH Z is OH]was prepared from 3-amino-5- (N-methylacetamido)-2,4,6-triiodobenzoicacid, 3-methylglutaric anhydride and sulfuric acid according to theprocedure of Example 1. The product was isolated in the free acid form,m.p. 301-302 C. (dec.) when recrystallized from acetic acid.

EXAMPLE 4 3,5-bis(Glutarimido)-2,4,6-triiodobenzoic Acid [A; R is (CH(CO) N, Y is CH,CH CH Z is OH].

a. From 3,5-diamino-2,4,6-triiodobenzoic acid. A mixture of 265 g. of3,5-diamino-2,4,6-triiodobenzoic acid, 400 g. of glutaric anhydride and18 ml. of concentrated sulfuric acid was heated at 100 C. and stirredfor 17 hours. The product was isolated and recrystallized from dimethylsulfoxide, adding water to induce precipitation, and was obtained as alight gray solid with one mole of dimethyl sulfoxide of crystallization,m.p. above 300 C. A sample of the acid was converted to its sodium saltform, m.p. 288291 C. (dec.) when recrystallized from water.

b. From 3-acetamido-5-amino-2,4,6-triiodobenzoic acid. A mixture of l1.4 g. of 3-acetamido-5-amino-2,4,6- triiodobenzoic acid, 23 g. ofglutaric anhydride and 1 ml. of concentrated sulfuric acid was heated ona steam bath for 2 95 hours. The reaction mixture was stirred with waterand the product (14.4 g. collected by filtration. The product wasrecrystallized twice from acetone to give 3,5-bis( glutarimido2,4,6-triiodobenzoic acid. The same compound is obtained if the3-acetamido-5-amino-2,4,6-triiodobenzoic acid is replaced by3,5-diacetamido-2,4,6-triiodobenzoic acid.

The following compounds were prepared following the procedure of Example1 from the appropriate 3-amino-5-R- 2,4,6-triiodobenzoic acid and acidanhydride:

Example 5: 3-(3,3-Dimethylglutarimido )-5-(N-methylacetamido)-2,4,6-triiodobenzoic Acid [A; R is CH CON(CH Y is CHC(CH CH Z is OH], pale tan solid, m.p. 274-278 C.(dec.) (from aceticacid); sodium salt form, pale yellow solid, m.p. 235-245 C.(dec.).

Example 6: 3-Glutarimido-5-(N-ethylacetamido)-2,4,6- triiodobenzoic Acid[A; R is CH CON(C H Y is CHgCHzCH, Z is OH], sodium salt form, m.p.above 220 C. Example 7: 3-(Methylsuccinimido)-5-(N-methylacetamido)-2,4,6-triiodobenzoic Acid [A; R is CH CON(CH Y is CH(CH )CH h Z is OH],m.p. 285-287 C. (from acetic acid); sodium salt form, m.p. above 245C.(dec.).

Example 8: 3-( Di g1 ycolimido )-5 N-methylacetamido )-2,4 ,6-triiodobenzoic Acid [A; R is CH CON(CH Y is CH OCH Z is OH], sodium saltform, m.p. 250-255 C(No sulfuric acid was used in this preparation.

Example 9: 3-( 3 ,S-Dioxothiomorpholino )-5- methylacetamido)-2,4,6-triiodobenzoic Acid [A; R is CH CON(CH Y is Ch SCH Z is 01-1],sodium salt form, beige solid, m.p. 250260 C.(dec.). No sulfuric acidwas used in this preparation.

3-( 3 ,S-Dioxothiomorpholino )-5-( N-methylacetamido2,4,6-triiodobenzoic acid can be oxidized with m-chloroperbenzoic acidin dimethylformamide solution to give 3- 3 ,5,S,S-tetraoxothiomorpholino )-5-( N-methylacetamido 2,4,6-triiodobenzoicacid [A; R is CH CON(CH Y is CH SO CH, Z is OH].

Example 10: 3-Glutarirnido-2,4,6-triiodo-N- methylisophthalamic Acid [A;R is CH NHCO, Y is CH CH CH, Z is OH], sodium salt form, light tansolid, m.p. 250-270 C.(dec.) when recrystallized from aqueous methanolwith addition of ether.

Example 1 1: 3-Succinimido-2,4,-triiodo-N- methylisophthalamic Acid [A;R is CH NHCO, Y is CH CH Z is OH], m.p. above 300 C.; sodium salt form,pale pink solid, m.p. 258-26l C.

Example 12: 5-Glutarimido-2,4,6-triiodoisophthalic Acid [A; R is HOOC, Yis CH CH CH Z is OH], m.p. above 300 C.; disodium salt form, whitesolid, m.p. above 300 C.

Example 13: 3-Succinimido-2,4,6-triiodobenzoic Acid [A; R is H, Y is CHCH Z is OH], colorless prisms, m.p. 27928 1 C. (from acetic acid).

Example 14: 3-( 3 ,5-Dioxothiomorpholino)-2,4,6- triiodobenzoic Acid [A;R is H, Y is CH SCH Z is OH], sodium salt form, light tan solid, m.p.274-284 C.(dec. Example 15: 3-( Diglycolimido )-2,4,6-triiodobenzoicAcid [A; R is H, Y is CH OCH Z is OH], sodium salt form, light beigesolid, m.p. 274-28 1 C.(dec.).

Example 16: 3-Glutarimido-2,4,6-triiodobenzoic Acid [A; R is H, Y is CHCH CH Z is OH], pale pink solid, m.p. 25025 1.5 C. (from acetic acid);sodium salt form, light lavender solid, m.p. 249-252.5 C.

Example 17: 3-Succinimidobenzoic Acid [K; R is H, X is H, Y is CH CH Zis OH], m.p. 237-239 C.; sodium salt form, m.p. l51-196C.

Example 18: 3-Glutarimidobenzoic Acid [K; R is H, X is H, Y is CH CH CHZ is OH], m.p. 272-275 C.; sodium salt form, m.p. about 110 C.

EXAMPLE 1 9 3'-Carboxy-5-(N-methylacetamido)-2', 4',6-triiodoglutaranilic Acid [8; R is CH CON(CH R and R are H, Y is CH CHCHB2, Z is OH].

A mixture of 58.6 g. of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid, 74 g. of glutaric anhydride and 8 ml. ofconcentrated sulfuric acid was heated on a steam bath for 5 hours. Thereaction mixture was poured into water and the solid product collectedby filtration. The product, consisting of 3-glutarimido-5-(N-methylacetamido)-2,4,6- triiodobenzoic acid (Example 1) was dissolvedin excess dilute aqueous sodium hydroxide, and the solution warmed for30 minutes, then cooled and 3N hydrochloric acid added slowly untilprecipitation was complete. The solid product was collected andrecrystallized first from acetone, then from acetic acid, and finallyfrom water to give 3-carboxy-5'-( N- methylacetamido)-2, 4,6'-triiodoglutaranilic acid, colorless prisms, m.p. l88.8196.0 C.

Similarly, by warming in dilute aqueous sodium hydroxide,3-glutarimido-5-(N-butylacetamido)-2,4,6-triiodobenzoic acid,3-glutarimido-5( N-methylpropionamido)-2,4,6- triiodobenzoic acid,3-glutarimido-5-( N-methylcaproylamino)-2,4,6-triiodobenzoic acid,3-glutarimido-5- (N,N-dimethylcarbamoyl)-2,4,6-triiodobenzoic acid,3-(2,3- dimethylsuccinimido )-5-( N-methylacetamido )-2,4,6-triiodobenzoic acid, 3-(2,3,4-trimethylglutarimido)-5-(N-methylacetamido)-2,4,6-triiodobenzic acid, 3-(2-methylglutarimido)--(N-methylacetamido)-2,4,6-triiodobenzoic acid, 3-( 3-methylglutarimido)-5-( N-methylacetamido)-2,4,6- triiodobenzoic acid, or3-glutarimido5-(N-methyl-Z-methoxyacetamido)-2,4,6-triiodobenzoic acidcan be hydrolyzed, respectively, to 3-carboxy-5'-(N-butylacetamido)-2,4', 6- triiodoglutaranilic acid [8; R is Ch CON(C H R and R" are H, Y isCH CH CH Z is OH], 3'-carboxy-5'-( N-methylpropionamido)-2, 4',6-trii0doglutaranilic acid [8; R is CH CH CON(CH R and R" are H, Y is CHCH CH Z is OH], 3-carboxy-5 N-methylcaproylamino)-2, 4', 6-triiodoglutaranilic acid [8; R is CH;,( CH CON(CH R and R" are H, Y isCH CH CH Z is OH], 3-carboxy-5-(N,N- dimethylcarbamoyl)-2, 4,6'-triiodoglutaranilic acid [B; R is (CH NCO, R and R" are H, Y is CH CHCH Z is OH], 3-carboxy-5'-(N-methylacetamido)-2, 4, 6-triiodo-2,3-dimethylsuccinanilic acid [8; R is CH CON(CH R and R are H, Y is CH(CH)CH(CH Z is OH], 3carboxy-5'-(N- methylacetamido)-2, 4,6'-triiodo-2,3,4-trimethylglutaranilic acid [B; R is CH CON(CH R and Rare H, Y is CH(CH )CH(CH Z is OH], 3'-carboxy-5-(N- methylacetamido)-2,4', 6-triiodo-2(or 4)-methylglutaranilic acid [8; R is CH CON(CH R and Rare H, Y is CH(CH )CH h or CH CH CH(CH;,), Z is OH], 3-carboxy- 5N-methylacetamido)-2', 4, 6'-triiodo-3-methylglutaranilic acid [3; R isCH CON(CH R and R are H, Y is CH CH(CH CH Z is OH], or3'-carboxy-5-(N-methyl-2- methoxyacetamido)-2', 4',6-triiodoglutaranilic acid [B; R is CH OCH CON(CH R and R" are H, Y isCH CH CH Z is OH].

3-Carboxy-5-(N-methylacetamido)-2, 4, 6-triiodoglutaranilic acid canalso be prepared by heating 3-amino-5-(N-methylacetamido)-2,4,6triiodobenzoic acid with 4-carbomethoxybutyrylchloride (CH-,OCOCH 'CH CH COCI) in dioxane solution, followed byhydrolysis of the resulting methyl 3-carboxy-5'-(N-methylacetamido)-2',4, 6'- triiodoglutaranilate by heating it with potassium carbonate inmethanol solution.

Similarly, 3-amino-5( N-methylacetamido )-2,4,6- triiodobenzoic acid canbe caused to react with Cl- COCH CH CH COOCl-l ClCOCH,CH-,OCH,CH,C OOCHor ClCOCH SCH CH CH CH SCH COOCH to give, respectively, the followingcompounds: [8; R is CH CON(CH,-,, R is H, R" is CH Y is CH CH CH CH,, Zis OH]; [8; R is CH CON(CH R is H, R" is CH Y is CH CH OCH CH Z is OH];or B; R is CH CON(CH R is H, R" is CH Y is CH SCH CH CH CH,SCH Z is OH].These can be hydrolyzed to the corresponding acids where R" is hydrogen.In the same manner, 3,5-diamino- 2,4,6- triiodibenzoic acid can becaused to react with Cl- COCH CH CH Coocl-l to give [3; R is CH OCOCH CH CH CH CONH, R is H, R is CH Y is CH,CH,CH CH,, Z is OH], which can behydrolyzed to give [8; R is HOC0CH CH h CH CONH, R and R" are H, Y is CHCH CHB2CH Z is OH].

EXAMPLE 2O 3-Carboxy-5-(N-methylacetamido) 2, 4, 6'-triiodosuccinanilicAcid [B; R is CH CO, R and R are H, Y is CH CH Z is OH]was prepared from34.3 g. of 3-amino-5-(N- methylacetarnido)-2,4,6-triiodobenzoic acid, 82g. of succinic anhydride and 5 ml. of concentrated sulfuric acid,followed by alkaline hydrolysis of the resulting 3-succinimido-5-( N-methylacetamido)-2,4,6-triiodobenzoic acid, according to the methoddescribed in Example 19. The product was recrystallized from diluteethanol and from a methanol-acetonitrile mixture and further purified byconverting it to the diammonium salt by means of ammonium hydroxide inmethanol, and then acidifying an aqueous solution of the ammonium saltto regenerate the free acid. There was thus obtained 3-carboxy- 5N-methylacetamido)-2 ',4',6'-triiodosuccinanilic acid, m.p. 275.0-276.0C. (dec.

EXAMPLE 2| 3-[2-(Carboxymethylsulfonyl )acetamido]-2,4,6-triiodo5-( N-methylacetamido)benzoic Acid [8; R is CH,-,CON(CH;,), R and R" are H, Yis CH SO CH Z is OH].

A solution of 26.1 g. of 3-amino-5-(N-methylaeetamido)-2,4,6-triiodobenzoic acid in 300 ml. of dioxane was distilled untilabout 60 ml. of dioxane was removed in order to eliminate possibletraces of water. Sulfonyldiacetyl chloride (CICOCH SO CHL-COCI) (5.85g.) was then added, and the mixture was stirred and refluxed for about 5days. The reaction mixture was concentrated in vacuo to remove thesolvent, and the residue was dissolved in dilute sodium hydroxide togive a solution of the sodium salt of the product. The basic solutionwas made weakly acid, which did not cause precipitation of the acid formof the product, treated with activated charcoal at 60 C. and filtered.The filtrate was acidified with 3N hydrochloric acid and theprecipitated product collected. The acid product was purified bydissolving it in ammonium hydroxide solution and reacidifying theresulting ammonium salt solution. The acid product was recrystallizedfrom aqueous dimethylformamide to give3-[2-(carboxymethylsulfonyl)acetamido]-2,4,6-triiodo-5-(N-methylacetamido)benzoicacid, m.p. above 300 C.

By replacing the Sulfonyldiacetyl chloride in the foregoing preparationby sulfoxydiacetyl chloride (ClCOCH SO-CH COCl) there can be obtained3[2-(carboxymethyl-sulfoxy)acetamido]-2,4,6-triiodo-5-(N-methylacetarnido)benzoic acid [8; R is CH CON(CH R and R are H, Y isCH SOCH,, Z is OH].

The following compounds were prepared either by mild alkaline hydrolysisof the corresponding cyclic imides, or directly from the appropriate3-amino-5-R-2,4,6- triiodobenzoic acid without isolation of theintermediate cyclic imide as described above in Examples 19 and 20.Example 22: 3'-Carboxy-2',4',6'-triiodo-3-methyl-5'-(N-methylacetamido)glutaranilic Acid [8; R is CH CON(CH R andR" are H, Y isCH CH(CH )CH Z is OH], colorless crystals, m.p. 256-259 C. (dec.

Example 23: 3,5 bis(4-Carboxybutyramido)-2,4,6- triiodobenzoic Acid [B;R is HOOC(CH CONH, R and R" are H, Y is CH CH CH Z is OH], colorlesssolid, m.p. 25 l-25 3 C. (from acetic acid).

Example 24: 3-Carboxy-2,4',6-triiodo-3,3dimethyl-5'-( N-methylacetamido)glutaranilic Acid [8; R is CH CON(CH,-,), R and R" areH, Y" is CH C(CH CH Z is OH], colorless crystals, m.p. 258-262 C. (dec.

Example 25: 3'-Carboxy-S'-(N-ethylacetamido)-2,4',6- triiodoglutaranilicAcid [8; R is CH CON(C H R and R" are H, Y is CH CH CH Z is OH],colorless solid, m.p. 250 C. (dec. Example 26:3'-Carboxy-2,4',6'-triiodo-3-methyl-5'-(N- methyl-acetamido)succinanilicAcid [8; R is CH CON(CH R and R" and H, Y is CH(CH )CH Z is OH], lightorange solid, m.p. 262-264 C. (dec.

Example 27: 3-Carboxy-2,4,6'triiodo-5'-(N-methylacetamido)-diglycolanilic Acid [8; R is CH CON(CH R and R" are H,Y is CH OCH Z is OH], disodium salt form, light tan solid, m.p. 245260C. (dec.

Example 28: 3-{2-(Carboxymethylthio)acetamido]-2,4,6- triiodo5-(N-methylacetamido)benzoic Acid I B; R is CH CON(CH R and R" are H, Y'is CH SCH Z is CH], beige solid mp. 165-l 70 C.

Example 29: 3'-Carboxy-2',4,6-triiodo5-methylcarbamoylglutaranilic Acid[8; R is CH NHCO, R and R" are H, Y is CH CH CHB2, Z is OH], pale pinkprisms, m.p. 2.49252 C.

(dec.

Example 30: 5 (4-Carboxylbutyramido)-2,4,6- triiodoisophthalic Acid [B;R is HOOC, R and R" are H, Y is CH CH CH Z is OH], colorless solid, m.p.238 C. (dec. Example 31: 3-Carboxy-2,4',6'-triiodosuccinanilic Acid [8;R, R and R" are H, Y is CH CH Z is OH], colorless prisms, m.p. 237-239C.(dec.).

Example 32: 3-[ 2-(Carboxymethylthio)acetamido]-2,4,6- triiodobenzoicAcid [8; R, R and R" are H, Y is CH SCH Z is OH], colorless solid m.p.237240 C.

Example 33: 3-Carboxy-2,4', 6'-triiododiglycolanilic Acid [3; R, R and Rand H, Y is CH OCH- Z is OH], colorless solid, m.p. 23 l-234 C.

Example 34: 3-Carboxy-2',4',6'-triiodoglutaranilic Acid {8; R, R and R"are H, Y is CH CH CH Z is OH], colorless crystals, m.p. 249-250 C.

Example 35: 3-Carboxysuccinanilic Acid [M; R is H, X is H, Y is CH CH Zis OH], colorless solid, m.p. 223225 C. Example 36:3'-Carboxyglutaranilic Acid [M; R is H, X is H, Y is CH CH CH Z is OH],pale tan crystals m.p. 22l224 C.

EXAMPLE 37 added to a heated solution of 540 g. of ferrous sulfateheptahydrate in 900 ml. of water. Concentrated ammonium hydroxide ml.was then added during l5 minutes in 50 ml. portions. After 30 minutes ofheating on a steam bath, the reaction mixture was filtered and made acidto pH 3.5. The product was collected and dried in vacuo over phosphoruspentoxide to give 57.5 g. of 3'carboxy-5'-aminosuccinanilic acid, m.p.194 C.(dec. d. 3'-Carboxy-5'-amino-2',4',6'-triiodosuccinanilic Acid [8;Ris NH R and R" and H, Y is CH CH Zis OH].

Potassium iododichloride (335 ml. 2.23N in water), was added over aperiod of 40 minutes to a stirred suspension of 57.3 g. of3carboxy-5'-aminosuccinanilic acid in 435 ml. of water. The solidproduct was collected by filtration and recrystallized from water andfrom aqueous dimethylformamide. The product was purified by convertingit to the diammonium salt and then to the disodium salt, m.p. 222225 C.(dec. The latter was acidified to produce the free acid form of3carboxy-5'-amino-2',4',6-triiodosuccinanilic acid, cream colored solid,m.p. l56.2l72.2 C.(dec.

3'-Carboxy-5-amino-2',4',6-triiodosuccinanilic acid can be acylated withacetic anhydride, using a few drops of perchloric acid as a catalyst toobtain 3-carboxy-5- acetamido-Z',4',6'-triiodosuccinanilic acid [13; Ris CH CONH, R and R" are H, Y is CH CH Z is OH].

EXAMPLE 3 8 a. 3Glutarimido-5-nitrobenzoic Acid ID; Y is cH CH CH- Z isOH]was prepared by heating a mixture of 18.2 g. of 3-amino-S-nitrobenzoic acid, 45.6 g. of glutaric anhydride and 0.5 ml. ofconcentrated sulfuric acid on a steam bath for 2 hours. The product wasisolated and recrystallized from aqueous dimethylforrnamide to give3glutarimido-5-nitrobenzoic acid, pale yellow prisms, m.p. above 300 C.b. 3'-Ca.rboxy-5"nitroglutaranilic Acid F; Y is CH CH CH Z is OH] wasprepared by warming gently a solution of 5.0 g. of3-glutarimido-5-nitrobenzoic acid in excess l0 percent aqueous sodiumhydroxide. The solution was acidified with 3N hydrochloric acid and theproduct collected and recrystallized from ethyl acetate to give3-carboxy-5'- nitroglutaranilic acid, pale yellow prisms, m.p. l82-184C. c. 3'Carboxy-5-aminoglutaranilic Acid [6; Y is CHZCHQCHQ Z is OH].

3-Glutarimido-5-nitrobenzoic acid (55.6 g.) was dissolved in ml. of 10percent aqueous sodium hydroxide, the pH adjusted to 8 with 3Nhydrochloric acid, 1.0 g. of 10 percent palladium-on-carbon catalystadded, and the mixture hydrogenated in a Parr apparatus. Reduction wascomplete in 5 hours. The reaction mixture wa filteredand the filtratecontaining 3-carboxy-5'-aminoglutaranilic acid iodinated as describedbelow.

d. 3'-Carboxy-5-amino-2,4',6'-triiodoglutaranilic Acid [B; R is HgN, Rand R" are H, Y is CH CH CH Z is OH].

The filtrate containing 3 '-carboxy-5'-aminoglutaranilic acid wasdiluted with water to 800 ml. j and 100 ml. of 6N hydrochloric acidadded, followed by 500 ml. of 1.28N sodium iododichloride. The reactionmixture was stirred for about [6 hours, sodium bisulfite solution addedto destroy excess iodine and the solid product collected. The latter wasconverted to its diammonium salt with ammonium hydroxide in isopropylalcohol, the salt collected, dissolved in water, and the solutionacidified with hydrochloric acid. The free acid was collected and driedat 60 C. to give 3-carboxy-5'-amino- 2',4,6-triiodoglutaranilic acid,m.p. 2l922 1 C. (dec.

EXAMPLE 39 a. 3-Glutarimido-5-aminobenzoic Acid [E; Y is CH CH CH Z isOH] can be prepared by reduction of 3-glutarimido-5- nitrobenzoic acid(Example 38a). The reduction can be carried out catalytically (platinumor nickel catalyst) under neutral or acidic conditions.

b. 3-Glutarimido-5-anfino-2,4,G-triiodobenzoic Acid [A; R is H N, Y isCH CH CH Z is OH] can be prepared by iodination of3-glutarimido-5-aminobenzoic acid with potassium iododichlorideaccording to the procedure described in Example 37, part ((1).

c. 3-Glutarimido-5acetamido-2,4,6-triiodobenzoic Acid [A: R is CH COHN,Y is CH CH CH Z is OH] can be prepared by acetylation of3-glutarimido-5-amino-2,4,6-triiodobenzoic acid with acetic anhydride,using a few drops of perchloric acid as a catalyst.

EXAMPLE 40 a. 3'-Carboxy-5-nitrodiglycolanilic Acid [F; Y is CH OCH Z isOH], pale yellow prisms, m.p. 2l6-219 C. (from water), was prepared from3-amino-5-nitrobenzoic acid and diglycolic anhydride.

b. 3'-Carboxy-5'-a.min0diglycolanilic Acid [G; Y is CH OCH Z is OH] wasprepared by hydrogenation of 3-carboxy-5- nitrodiglycolanilic acid withpalladium-on-carbon catalyst. It was iodinated in the following stepwithout purification.

c. 3 '-Amino-5 -carboxy-2' ,4 ,6'-triiododiglycolanilic Acid [B; R is HN, R and R" are H, Y is CH OCH Z is OH], pale cream-gray prisms, m.p.220223 C. (dec.) (from acetic acid), was prepared by iodination of3-carboxy-5- aminodiglycolanilic acid with potassium iododichloride.

EXAMPLE 41 3 -Carboxy-5 -amino-2 ,4 ,6-triiodo-N-methylglutaranilic Acid[B; R is H N, R is CH R" is H, Y is CH CH CH Z is OH].

To a solution of 26.0 g. of 3-carboxy-5-amino-2',4,6-triiodoglutaranilic acid (Example 38, part d) in 100 ml. of 10 percentaqueous sodium hydroxide cooled in an ice bath was added 8 ml. ofdimethyl sulfate in acetone. After 3 hours of stirring an additional ml.of 10 percent sodium hydroxide and 2 ml. of dimethyl sulfate were addedand the mixture stirred 3 hours longer. The reaction mixture wasacidified, and the product collected and recrystallized from acetic acidto i give 3 '-carboxy-5 -amino-2 4,6-triiodoN-methylglutaranilic acid,pale gray crystals, m.p. 218-220 C. (dec.

EXAMPLE 42 3 -Carboxy-5 -glutarimido-2 ,4,6'-triiodo-N-methylglutaranilic Acid [A; R is HOOC(CH CON(CH;,), Y isCH,CH CH, Z is OH] was prepared from 3-carboxy-5-amino-2',4,6-triiodo-N-methylglutaranilic acid (Example 41) and glutaricanhydride according to the procedure of Example l. The free acid wasobtained as a colorless solid, m.p. l60-l61 C. when recrystallized fromacetic acid, and the disodium salt form as a beige solid, m.p. 252255 C.

EXAMPLE 43 3 '-Carboxy-5 N-methylacetamido )-2 ,4 ,6-triiodo-N-methylglutaranilic Acid [B; R is CH CON(CH R is CH R" is H, Y is CH,CHCH Z is OH] was prepared from 49.0 g. of3-carboxy-5'-(N-methylacetamido)-2,4,6-triiodoglutaranilic acid (Example19) and 15 ml. of dimethyl sulfate in 175 ml. of 10 percent sodiumhydroxide according to the procedure of Example 41. The product wasrecrystallized from acetic acid, using ethyl acetate to bring thecompound out of solution. There was thus obtained 3'-carboxy-5-(N-methylacetamido)-2',4,6-triiodo-N-methylglutaranilic acid, colorlessprisms, m.p. 284-287 C. (dec.

EXAMPLE 44 3 '-Carboxy-5 N-methylacetamido )-2' ,4 6'-triiodo-N-ethylglutaranilic Acid [B; R is Cl-LCON(CH,), R is C H R" is H, Y is CHCH,CH,, Z is OH] was prepared from 56,3 g. of3-carboxy--N-methylacetamido)-2,4,6-triiodoglutaranilic acid (Example19) and 40 ml. of diethyl sulfate in 10 percent sodium hydroxidesolution according to the procedure of Example 41. The product wasrecrystallized from acetic acid and from an acetic acid-ethyl acetatemixture to give 3-'carboxy-5 Nmethylacetamido )-2 ,4,6-triiodo-N-ethylglutaranilic acid, m.p. 25926l C. (dec.

3-Carboxy-5-(N-methylacetamido)-2,4,6-triiodoglutaranilic acid cansimilarly be alkylated with n-butyl iodide, 2- hydroxyethylbromide,2-ethoxyethyl bromide or 2-( Z-ethoxyethoxy)ethyl p-toluenesulfonate togive 3-carboxy-5-(N- methylacetamido)-2,4,6'-triiodo-N-butylglutaranilicacid [B; R is CH CON(Cl-I R is C H R is H, Y is CH,CH,CH Z is OH],3-carboxy-5'-(N-methylacetamido)-2,4',6'- triiodo-N-(2-hydroxyethyl)glutaranilic acid [B; R is Cl-i CON(CH-,, R is HOCH CH R"is H, Y is CH,CH,CH,, Z is OH]; 3'-carboxy-5-(N-methylacetamido)-2',4,6-triiodo-N-( 2-ethoxyethyl)glutaranilic acid [B; R is CH CON(CH R isC,H,,OCH,CH R is H, Y is CH CH CH, Z is OH] or 3 'carboxy-5 N-methylacetamido)-2,4,6-triiodo-N-[2-(2-ethoxyethoxy)ethyl]glutaranilicacid [B; R is Cl-L,CON(CH;), R is C,H,OCHCH OCH CH,, R" is H, Y is CHCH,CH,, Z is OH].

According to the procedure of Example 41, the following compounds wereprepared: Example 45: 3'-Carboxy-2,4,6-triiodo-3,N-dimethyl-5'-(N-methylacetamido)glutaranilic Acid [B; R is CH CON(CH R is CH R is H, Yis CH,CH(CH,)CH,, Z is OH], colorless solid, m.p. 22l-222 C. (fromacetic acid), prepared by methylation of3-carboxy-2',4,6-triiodo-3-methyl-5-(N- methylacetamido )-glutaranilicacid (Example 22). Example 46:3,5,-bis(4-Carboxy-N-methylbutyramido)-2,4,6- triiodobenzoic Acid [B; Ris HOOC(Cl-I CON(CH R is CH R is H, Y is CH CH CH Z is OH], colorlessprisms, m.p. 234-236 C. (from acetic acid), prepared by methylation of3,5-bis(4-carboxybutyramido)-2,4,6-triiodobenzoic acid (Example 23).Example 47: 3-Carboxy-2',4',6'-triiodo-N-methyl-5'-(N-methyl-acetamido)diglycolanilic Acid [B; R is CH -,CON(CH R is CH, R" isH, Y is CHgOCHz, Z is OH], colorless solid, m.p. 267272 C., prepared bymethylation of 3'-carboxy-2,4',6-triiod0-5'-(N-methylacetamido)diglycolanilic acid(Example 27). Example 48: 3-[2-(Carboxymethylthio)-N-methylacetamido]-2,4,6-triiodo-5-(N-methylacetamido)benzoic Acid [B; R is CH -,CON(CH,-,,R is CH. R" is H, Y' is CH SCH Z is OH], light tan solid, m.p. 260265 C.(dec. prepared by methylation of3-[2-(carboxymethylthio)acetamido]-2,4,6- triiodo-5-(N-methylacetamido)benzoic acid (Example 28). Example 49:3-Carboxy-2,4,6-triiodo-N-methylglutaranilic Acid [B; R is H, R is CH,,,R" is H, Y is CH,CH,CH Z is OH], colorless solid, m.p. 230-23l C. (fromacetic acid), prepared by methylation of3'-carboxy-2',4,6-triiodoglutaranilic acid (Example 34). Example 50:3-Carboxy-2',4,6-triiodo-N-methylsuccinanilic Acid [B; R is H, R is CH Ris H, Y is CH CH,, Z is OH], colorless solid, m.p. 245249 C. (fromacetonitrile), prepared by methylation of3-carboxy-2,4,6-triiodosuccinanilic acid (Example 31 Example 5 l: 3'-Carboxy-2',4',6'-triiodo-5-( N-methylacetamido)-3,3,N-trimethylglutaranilic Acid [B; R is CH CON(CH Ris CH,,, R" is H, Y is CH C(CH ),CH,, Z is OH], m.p. l83l84.5 C.,prepared by methylation of 3- carboxy-Z',4,6'-triiodo-3,3-dimethyl 5-(N-methylacetamido )glutaranilic acid (Example 24).

EXAMPLE 52 Methyl 3-carboxy-2,4,6-triiodo-5'-(N-methylacetamido)-adipanilate [B; R is CH-,CON(CH,,), R is H, R is CH Y is (CH 2 is CH].

A mixture of 98.4 g. of adipic acid monomethyl ester and 500 ml. ofthionyl chloride was refluxed for 1 hour. The excess thionyl chloridewas then removed in vacuo, and the last traces of thionyl chloride wereremoved by adding benzene and concentrating the solution. To the residuewas added 260 g. of 3-amino-5-(N-methylacetarnido)-2,4,6-triiodobenzoicacid in 3,500 ml. of dioxane. The mixture was refluxed for about 36hours and allowed to stand for 2 days at room temperature. The solidproduct was collected and recrystallized from acetic acid to give methyl3'-carboxy-2',4',6'-triiodo-5, (N-methylacetamido)-adipanilate as acolorless solid, mp: 229-232 C.

Methyl 3-carboxy-2', 4',6'-triiodo-5'-(N-methylacetamido)adipanilate wasobtained in the form of its sodium salt by treating the free acid withmethanolic sodium hydroxide. The sodium salt had the m.p. 264-267 C.(dec.

EXAMPLE 53 3 -Carboxy-2 ,4 ,6'-triiodo-5 N-methylacetamido )adipanilicAcid [B; R is CH CON(CH R and R" are H, Y is (CH ),,Z is OH].

To a mixture of 143.8 g. of methyl 3'-carboxy-2,4,6'-triiodo5'-(N-methylacetamido)adipanilate (Example 52) and 150 ml. ofwater was added dropwise 145 ml. of percent sodium hydroxide solution.The reaction mixture was heated on a steam bath for 2 hours and thencooled and acidified with 3N hydrochloric acid solution. The solidproduct was collected and recrystallized from acetic acid to give3'-carboxy- 2',4,6-trii0do-5-(Nmethylacetamido)adipanilic acid in theform of a colorless solid, m.p. 26727 1 C. (dec.

EXAMPLE 54 3'-Carboxy-2,4',6'-triiodo-N-methyl-5-(N-methylacetamido)-adipanilic Acid [B; R is CH CON(CH R is CH R is H, Y is(CH;),,, Z is OH] was prepared by methylation of 3'-carboxy-2',4',6'-triiodo-5 N- methylacetamido)adipanilic acid (Example53) with dimethyl sulfate according to the procedure described inExample 4l. The product was purified through the sodium salt and thenrecrystallized from acetic acid to give 3'-carboxy-2',4',6'-triiodo-N-methyl-5-(N-methylacetamido)adipanilic acid in the form of acolorless solid, m.p. l94-204 C.

EXAMPLE 55 2,4 ,6-Triiodo-3- 3-[ 2-( methoxycarbonyl )ethylthio]propionarnido -5-( N-methylacetamido)benzoic Acid [B; R is CH CON(CH Ris H, R" is CH Y is CH CH SCH CH Z is OH] was prepared from 225 g. of3-amino-5-(N- methylacetamido)-2,4,6-triiodobenzoic acid and 80.52 g. ofClCOCH Cl-l SCH CH COOCH in 1,170 mi. of dioxane according to theprocedure described above in Example 52. The product was recrystallizedfrom a methanol-acetonitrile mixture and was obtained as a colorlesssolid, m.p. 230240 C. (dec.

The sodium salt form of 2,4,6-triiodo-3- 3-[2-(rneth0xycarbonyl)ethylthio lpropionamido -5-( N- methylacetamido)benzoic acid, preparedfrom the free acid and methanolic sodium hydroxide, was obtained as acolorless solid, mp. 220-270 C.

EXAMPLE 56 EXAMPLE 57 Methyl 3 -carboxy-2 ,4 ,6-triiodo-5 '-(N-methylacetamido)- azelanilate [B; R is CH3CON(CH R is H, R is CH3, Y is(CH;)-,, Z is OH].

A mixture of g. of azelaic acid monomethyl ester and 500 ml. of thionylchloride was refluxed for 1 hour. The excess thionyl chloride wasremoved by distillation and the last traces removed by adding benzeneand evaporating the solvent. A solution of 260 g. of3-arnino-5-acetamido-2,4,6-trii0dobenzoic acid in 3,500 ml. of dioxanewas then added to the resulting acid chloride of azelaic acid monomethylester, and the mixture was refluxed for 6 hours. The dioxane was thenremoved by distillation and the residual product recrystallized fromacetic acid to give methyl 3-carboxy-2,4',6-triiodo-5-(N-methyl-acetamido)azelanilate, as colorless needles, mp. 198203 C.

By replacing the azelaic acid monomethyl ester by a molar equivalentamount of oxalic acid monomethyl ester or malonic acid monomethyl ester,there can be obtained, respectively, methyl3'-ca.rboxy-2',4',6'-triiodo-5'-(N- methylacetamido )oxalanilate 1B; Ris CH CON(CH R is H, R" is CH Y is single bond, 2 is OH], or methyl3'-carboxy- 2',4,6'-triiodo-5-(N-methylacetamido)malonanilate [B; R isCI-i CON(Cl-l,,), R is H, R" is Cl-i,, Y is CH 2 is OH].

The sodium salt form of methyl 3-carboxy-2',4', 6'-triiodo- 5'-( Nmethylacetamido)azelanilate was obtained in the form of a colorlesssolid, m.p. l97204 C. (dec.

EXAMPLE S8 3 '-Carboxy-2 ,4 ,6-triiodo-5 N-methylacetamido )azelanilicAcid [B; R is CH CON(CH R and R" are H, Y' is (Cl-l Z is OH].

A mixture of 136.5 g. of methyl 3'-carboxy-2',4,6'-triiodo-5'-(N-methylacetamido)azelanilate and 180 ml. of water was treated with10 percent aqueous sodium hydroxide (about ml.), added dropwise untilsolution was complete. The mixture was heated on a steam bath for 10minutes, 18 ml. more of l0 percent sodium hydroxide was added, and themixture heated 1 hour longer. The reaction mixture was cooled, acidifiedwith 3 percent hydrochloric acid, and the solid product collected,washed with water, dried and recrystallized from acetic acid to give3-carboxy-2',4',6'-triiodo-5'-(N- methylacetamido)azelanilic acid as acolorless solid, m.p. 205208 C. I

By replacing the methyl 3'carboxy-2',4,6'-t.riiodo-5'-(N-methylacetamido)azelanilate by a molar equivalent amount of methyl 3'-carboxy-2' ,4',6'-triiodo-5 N-methylacetamido oxalanilate or methyl3'-carboxy-2',4,6'-triiodo-5-(N- methyl-acetarnido)malonanilate therecan be obtained, respectively, 3 '-carboxy-2',4' ,6'-tr1'iodo-5 N-methylacetarnido)oxalanilic acid [B; R is CH CON(CH R and R" are H, Yissingle bond, Z is OH] or 3'-carboxy-2',4',6-triiodo-5'-(N-methylacetamido)-malonanilic acid [B; R is CH CON(CH Rand R" are H, Y is CH Z is OH].

EXAMPLE 59 methylacetamido )-azelanilic Acid [B; R is CH CON(CH R is CHR" is H, Y is (CH Z is OH] was prepared by methylation of3'-carboxy-2',4',6'-triiodo-5-(N- methylacetamido)azelanilic acid(Example 58) with dimethyl sulfate according to the procedure of Example41, and was obtained as a colorless solid, mp. 2 l0215 C., whenrecrystallized from ethyl acetate.

EXAMPLE 60N-{2,4,6-Triiodo-3-(acetylaminomethyl)-5-carboxyphenyl]glutarimide [A; Ris CH CONI-ICH Y is CH CH,CH Z is OH] was prepared by interacting3-acetamido-5- acetamidomethyl-2,4,6-triiodobenzoic acid with glutaricanhydride according to the method of Example i and was obtained in theform of a colorless solid, mp. 256268 C., when recrystallized fromacetic acid.

The sodium salt form ofN-[2,4,6-triiodo-3-(acetylaminomethyl)-5-carboxyphenyl]glutarimide wasobtained as a colorless solid, m.p. 252256 C.

EXAMPLE 61 N-[2,4,6-Triiodo-3-(acetylaminomethyl)--carboxyphenyl]glutaramic Acid [B; R is CH CONHCH Rand R" are H, Y is CH CH CH Z is OH] was prepared by hydrolysis of N-[2,4,6-triiodo-3-( acetylaminomethyl )-5-carboxyphenyl]glutarimide(Example 60) with dilute sodium hydroxide, and was obtained in the formof a colorless solid, mp. 234239 C. when recrystallized from aceticacid.

EXAMPLE 62 EXAMPLE 63 EXAMPLE 64 a.3-Amino-2,4,6-tn'iodo-5-(N-methylacetamido)-N,N- dimethyl-benzamide [C;R is CH CON(CH Q is H, Z is 92] The acid chloride (16.23 g.) preparedfrom 3-amino-5-(N- methylacetamido)-2,4,6-triiodobenzoic acid andthionyl chloride was interacted with 60 ml. of dimethylamine (40 percentin water), 20 ml. of 35 percent aqueous sodium hydroxide and 30 ml. ofwater. The product was isolated and recrystallized from isopropylalcohol to give 3amino-2,4,6-triiodo5-(N-methylacetamido)-N,N-dimethylbenzamide as a pale yellowsolid, mp. 235240 C. b. 3Glutarimido-2,4,6-triiodo-5-(N-methylacetarnido)-N,N- dimethylbenzamide[A; R is CH CON(CH Y is CH CH CH Z is N(CH was prepared from3-amino-2,4,6-triiodo-5- (N-methylacetamido) -N,N-dimethylbenzamide andglutaric anhydride according to the procedure described above in Examplel, and was obtained as a colorless solid, mp 299303 C. whenrecrystallized from aqueous dimethylformamide.

EXAMPLE 65 methylacetamido)-glutaranilic Acid [B; R is CH CON(CH R andR" are H, Y is CH CH CH Z is N(CH was prepared by hydrolysis of3-glutarimido-2,4,6-triiodo-5-(N- methylacetamido)-N,N-dimethy1benzamide(Example 64, part b) with dilute sodium hydroxide according to theprocedure of Example 19, and was obtained as a colorless solid, m.p.265268 C. when recrystallized from acetic acid.

EXAMPLE 66 3'-(Dimethylcarbamoyl)-2,4,6-triiodo-5-(N-methylacetamido)-N-methylglutaranilic Acid [B; R is CH CON(CH R is CH ZR" is H, Y is CH CH CH Z is N(CH was prepared by methylation of3-(dimethylcarbamoyl )-2,4 ,6'5 N-methylacetamido )-glutaranilic acid(Example 65) with dimethyl sulfate according to the procedure of Example41, and was obtained as a colorless solid, m.p. 209-214 C.

EXAMPLE 67 2,4,6-Triidodo-3-(N-methylacetamido)-5-(3-methylglutarirnido)- N,N-dimethylbenzamide [A; Ris CH CON(Cl-l Y is CH- -CH(CH::)CH2, Z is N(CH.)!] was prepared from 3-amino-5-(N-methylacetamido)- 2,4,6-triiodobenzoic acid and3-methylglutaric anhydride according to the procedure described inExample 1, and was obtained as a colorless solid, mp. 275-282 C. whenrecrystallized from acetic acid.

EXAMPLE 68 3 Dimethylcarbamoyl )-2 ,4',6',-triiodo-5 N-methylacetamido)- 3-methylglutaranilic Acid [B; R is CH CON(CH,-,, R andR" are H, Yis CH CH(CH )CH Z is N(CH was prepared by hydrolysis of2,4,6-triiodo-3-(N- methylacetamido)5-(3-methylglutarimido)-N,N-dimethylbenzamide (Example 67) with dilute sodium hydroxideaccording to the procedure described in Example 19, and was obtained asa colorless solid, mp. 244-254 C. when recrystallized from isopropylalcohol.

EXAMPLE 69 a. 4-[ 3-Amino-2,4,6-triiodo-5-( N-methylacetamido )benzoylmorpholine [C; R is CH,-;CON(CH,,), Q is H, Z is morpholine] wasprepared from the acid chloride of 3-amino-5-(N-methylacet-amido)-2,4,6-triiodobenzoic acid and morpholineaccording to the procedure described in Example 64, part (a). Theproduct obtained was used directly in the procedure described in part b)below.

By replacing the morpholine by piperidine or pyrrolidine there can beobtained, respectively, l-[3-amino-2,4,6-triiodo-5-(N-methylacetamido)benzoyl]piperidine [C; R is CH CON(CH Q is H, Z ispiperidino] or l-[3-amino-2,4,6-tn'iodo-5-(N-methylacetamido)benzoyl]pyrrolidine [C; R is CH CON(CH,, Qis H, 2 is pyrrolidino].

b. 4-[3-Glutarimido-2,4,6-triiodo-5-(N-methylacetamido)-benzoyl1morpholine [A; R A is CH CON(CH Y is CH CH2CH2, Z is morpholine]was prepared from 4-[3-amino-2,4,6-triiodo-5-(N-methylacetamido)benzoyl] morpholine andglutaric anhydn'de according to the procedure of Example 1, and wasobtained as a colorless solid, mp 293-299 C. when recrystallized fromacetic acid.

By replacing the4-[3-amino-2,4,6-triiodo-5-(N-methylacetamido)benzoyl]morpholine by1-[3-amino-2,4,6-triiodo- 5-(N-methylacetamido)benzoyl]piperidine orl-[3-amino- 2 ,4,6-triiodo-5-( Nmethylacetamido )benzoyl ]pyrrolidine,there can be obtained, respectively, l-[3-glutarimido-2,4,6-triiodo-5-(N-methylacetamiodo)benzoyl]piperidine [A; R isCl-L-,CON(Cl-L,, Y is CH CH CH Z is piperidion] or l-[3-glutarimido-2,4,6-triiodo-5-( N-methyl-acetamido )benzoyl pyrrolidine[A; R is'CH CON(CH Y is CH CH CH Z is pyrrolidino].

EXAMPLE 70 2', 4,6'-Triiodo-3 N-methylacetamido )-5 morpholinocanbonyl)-glutaranilic Acid [B; R is CH CON(CH R and R" are H, Y is CH CHCH Z is morpholine) was prepared by hydrolysis of4-[3-glutarimido-2,4,6-triiodo-5-(N- methylacetamido)benzoyl]morpholine(Example 69, part b) with dilute sodium hydroxide according to theprocedure of Example 19, and obtained as a colorless solid, mp. 28 l284'EXAMPLE 71 2 ,4 ,6-Triiodo-3 N-rnethylacetamido )-5morpholinocarbonyl)-N-methylglutaranilic Acid [8; R is CH CON(CH R is CHR" is H, Y'is CH CH CH Z is morpholino] was prepared by methylation of2',4',6'-triiodo-3-(N-methylacetamido)-5-(morpholinocarbonyl)glutaranilic acid (Example 70)with dimethyl sulfate according to the procedure of Example 4i. and wasobtained in the form of colorless crystals, mp. 25 l-257 C.

EXAMPLE 72 3,5-bis( Glutarimido )-2,4,6-triiodo-N-methylbenzamide [A; Ris glutarimido, Y is CHzCHzCHz. Z is NHCHnl was prepared from the acidchloride of 3,5'-bis(glutarimido)-2.4,6-triiodobenzoic acid) from thecompound of Example 4 and thionyl chloride) and aqueous methylaminesolution according to the procedure described in Example 64, part (a),and was obtained in the form of pale tan prisms, m.p. 27l272 C. (dec)when recrystallized from acetic acid.

EXAMPLE 73 EXAMPLE 74 3,5-bis(Glutarimido)-2,4,6-triiodo-N,Ndimethylbenzamide [A; R is glurarimido, Y is CH CH CH Z is N(CH3)2] wasprepared from the acid chloride of 3,5-bis(glutan'mido)-2,4,6-triiodobenzoic acid (Example 4) and aqueous dimethylamine according tothe procedure of Example 64, part (a), and was obtained in the form ofcolorless crystals, m.p. above 340 C. when recrystallized fromacetonitrile.

EXAMPLE 75 N,N-[ 2,4,6-Triiodo-5-( dimethylcarbamoyl)-m-phenylene]bis(glutar-amic Acid) [13; R is HOOC(CH );,CONH, R and R"are H, Y is CH CH CH Z is N(CH was prepared by hydrolysis of3,5-bis(glutarimido)-2,4,6-triiodo-N,N- dimethylbenzamide (Example 74)with sodium hydroxide, and was obtained as a colorless solid, mp.244-246 C.

EXAMPLE 76 3,S-bis(Succinimido)-2,4,6-triiodobenzoic Acid [A; R issuccinimido, Y is CH CH CH Z is OH] was prepared from 50 g. of3,5-diacetamido-2,4,6-triiodobenzoic acid and l50 g. of succinicanhydride in the presence of 5 ml. of concentrated sulfuric acid, 30minutes at 134 C., and was obtained in the form of pale cream crystals,m.p. above 300 C. when recrystallized from acetic acid.

EXAMPLE 77 N,N 5-Carboxy-2 ,4,6-triiodo-m-phenylene )disuccinamic AcidB; R is HOOCH CH CONH, R and R are H, Y is CH CH Z is OH] was preparedby hydrolysis of 3,5-bis(succinimido )-2,4,6-triiodobenzoic acid(Example 76) with dilute sodium hydroxide, and was obtained in the formof pale tan crystals, m.p. 229-230 C. (dec. when recrystallized fromacetic acid.

EXAMPLE 78 V a. 5-Arnino-2,4,6-triiodo-N,N,N,N-tetramethylisophthalamide1C; R is (Ch NCO, Q is H, 2 is N(Ci-h) A mixture of 66.80 g. of3-amino-2,4,6triiodoisophthalic acid and 200 ml. of thionyl chloride washeated with stirring on a hot water bath (75 C.) for 30 minutes. Theexcess thionyl chloride was removed by concentration in vacuo, and byadding benzene and evaporating the solvent. To the residue was slowlyadded 200ml. of dimethylamine (40 percent in water), followed by amixture of 66 ml. of 35 percent aqueous sodium hydroxide and 66 ml. ofwater. The reaction mixture was stirred for minutes and the solidproduct was collected and fractionally crystallized from methanol toobtain S-amino- 2,4,6-triiodo-N,N.N',N-tetramethylisophthalamide in twoisomeric forms; isomer A, colorless solid, mp. 244-260 C. and isomer B,beige crystals, m.p. 264-267 C.

b. 3-Giutarimido-2,4,6-triiodo-N,N,N',N'- tetramethyisophthalamide [A; Ris (CH; )gNCO, Y is (fine colorless needles from methanol) were preparedfrom 5- amino-2,4,6-triiodo-N,N,N',N-tetramethylisophthalamide (Example78, part a), isomers A and B, respectively, and glutan'c anhydrideaccording to the procedure of Example 1.

EXAMPLE 7 9 3',5 '-bis( Dimethylcarbamoyl )-2'4',6'-triiodogluta.ranilicAcid [8; R is (CH NCO, R and R" are H, Y is CH CH CH, Z is N(CH isomerA, m.p. 277-28l C. (colorless solid from methanol), and isomer B, m.p.274-275 C., were prepared by hydrolysis of3-glutarimido-2,4,6-triiodo-N,N,N' ,N'-tetramethylisophthalamide(Example 78, part b), isomers A and B, respectively, with dilute sodiumhydroxide.

EXAMPLE 80 3 ,5 '-bis( Dimethylcarbamoyl )-2',4',6-triiodooxalanilicAcid (B; R is (CH NCO, R and R" are H, Y is single bond Z is isomer B)in the form of colorless needles, mp. 20 l -2l 1 C.

EXAMPLE 8i Dimethyl 5amino-2,4,6-triiodoisopht.haiate [C; R is CH OOC, Qis H, 2 is OCH The acid chloride prepared from 25 g. of 5-amino-2,4,6-triiodiosopthalic acid and thionyl chloride was dissolved in ml. of drybenzene and 2.5 g. of sodium methoxide was added. The reaction mixturewas stirred at room temperature and the resulting product isolated togive dimethyl S-amino- 2,4,6-triiodoisophthalate as a tan solid, mp.l63-l 66 C.

By replacing the sodium methoxide by sodium ethoxide there was prepareddiethyl 5-amino-2,4,6-triiodoisophthalate, tan prisms, m.p. l45-150 C.

Dimethyl 5-amino-2,4,6-triiodoisophthalate can be interacted withglutaric anhydride according to the procedure of Example 1 to givedimethyl 3-glutarimido-2,4,6- triiodoisophthalate (A; R is CH OOC, Y isCH CH cH Z is OCH The latter can be hydrolyzed with dilute sodiumhydroxide to give first 3',5-dicarbomethoxy-2',4'36'-triiodoglutaram'lic acid [8; R is CH OOC, R and R" are H, Y is CH CH CHZ is OCi-ifland then 3',5'-dicarboxy-2',4,6- triiodoglutaranilic acid[8; R is HOOC, R and R" are H, Y is CH Cl-l Chbh2, Z is OH ](Example30).

EXAMPLE 82 a. -Amino-2,4,6-triiodo-N,N', -dimethylisophthalamide [C; Ris CH NHCO, Q is H, Z is NHCH was prepared from the acid chloride of5-amino-2,4,6-triiodoisophthalic acid and aqueous methylamine accordingto the procedure of Example 64, part (a), and was obtained in the formof tan crystals, m.p. 321314 C. when recrystallized from aqueousdimethylformamide.

By replacing the methylamine by ammonia there can be obtained5-amino-2,4,6-triiodoisophthalamide [C; R is H NCO, Q is H, 2 is NH b. 3,5 '-bis( Methylcarbomoy1)-2 ,4 ,6-triiodooxalanilic Acid [8; R is CHNHCO, R and R are H, Y is single bond, Z is NHCl-lflwas prepared from5-amino-2.4.6-triiodo-N,N- dimethylisophthalamide and ethyl oxalylchloride according to the procedure described in Example 80, and wasobtained in the form of a colorless solid, m.p. 275-285 C.

By replacing the 5-amino-2,4,6-triiodo-N,N- dimethylisophthalamide by5-ami.no-2,4,6 triiodoisophthalamide' there can be obtained 3',5-40-dicarbamoyl-2',4',6- triiodooxalanilic acid [8; R is H NCO, R and R"are H, Y is single bond, 2 is NH EXAMPLE 8 3 a.3-Nitro-5-(3,6,9-trioxadecanamido)benzoic Acid [6; T is CH OCH CH,OCH,CHOCH Z is OH A mixture of 14.6 g. of 3-amino-5-nitrobenzoic acid and 17.1g. of 3,6,9-trioxadecanoic acid chloride in 200 ml. of dioxane washeated at reflux for 24 hours. The reaction mixture was concentrated toremove the solvent. The residue was dissolved in dilute sodium hydroxideand then acidified with hydrochloric acid. The resulting product (13.6g., m.p. 130C.) was recrystallized from acetonitrile to give 3-nitro-5-(3,6,9-trioxadecanamido)benzoic acid as a beige solid, m.p. 136-l 37 C.

b. 3-Amino-5-(3,6,9-trioxadecanamido)benzoic Acid [H; T is CH=OCH,CH OCHCH OCH Z is CH ]was prepared by hydrogenation of 80 g. of3-nitro-5-(3,6,9-trioxadecanamido )benzoic acid in absolute ethanol inthe presence of palladium-on-charcoal catalyst. There was thus obtained54.7 g. of 3-amino5-(3,6,9-trioxadecanamido)benzoic acid, m.p, l30.5-13lC. when recrystallized from isopropyl alcohol.

c. 3-Amino-2,4,6-triiodo-5-(3,6,9-trioxadecanamido)benzoic Acid [1; T isCH OCH CH OCH CH OCH Z is OH ]was prepared by iodination of3-amino-5-(3,6,9-trioxadecanamido)benzoic acid with sodiumiododichloride according to the procedure of Example 37, pan (d), andwas obtained in the form of a tan solid, m.p. l77178 C. whenrecrystallized from methanol and a methanol-benzene mixture.

d. 3-Amino-2,4,6-triiodo-5-(N-methyl-3,6,9-trioxadecanamido )-benzoicAcid [C; R is H(CH,OCH CON(CH Q is H, Z is OH ]was prepared bymethylation of 3-amino-2,4,6-triiodo-5-( 3,6,9-trioxadecanamido)benzoicacid with dimethyl sulfate according to the procedure of Example 41, andwas obtained as an amorphous pink solid, m.p. l0O-109 C. whenrecrystallized from methanol.

EXAMPLE 84 a. 3-Cyclopropylcarboxa.mido-S-nitrobenzoic Acid [6; T is Asolution prepared from 89.5 g. of3-cyclopropy1carboxamido-S-nitrobenzoic acid and 142 ml. of 2.5N sodiumhydroxide was hydrogenated in the presence of 3 g. of 10 percentpalladium-on-carbon catalyst. The catalyst was removed by filtration andthe filtrate acidified. The product was collected and dried to give 62.5g. of 3-cyclopropylcarboxamido- S-arninobenzoic acid.

c. 3-Amino-5-(cyclopropylcarboxamido)-2,4,6-triiodobenzoic Acid [.1; Tis cyclopropyl, Z is OH].

To a solution of 62.1 g. of 3-cyclopropylcarboxamido-5- nitrobenzoicacid and ml. of 3N hydrochloric acid in 750 ml. of water was added 330.5m1. of 2.837N' aqueous sodium iododichloride solution over a period of27 minutes. The reaction mixture was heated at about C.- forseveral'days, and the product was isolated and recrystallized from anisopropyl alcohol-methanol mixture to give3-amino-5-(cyclopropylcarboxamido)-2,4,6-triiodobenozic acid, light tansolid, m.p. 224 C. (dec.

d. 3-Amino-5-(N-methylcyclopropylcarboxamido)-2,4,6- triiodobenzoic Acid[C; R is cyc1opropyl-CON(CH Q is H, ZisOH].

A solution of 59.8 g. of3-amino-5-(cyclopropy1carboxamido)-2,4,6-triiodobenzoic acid in 320 ml.of 10 percent sodium hydroxide solution was treated with 25.2 g. ofdimethyl sulfate in 50 ml. of acetone. The product was isolated andpurified by conversion to the sodium salt and back to the free acid, andby recrystallization from isopropyl alcohol, to give3-amino-5-(N-rnethylcyclopropylcarboxamido)-2,4,6-triiodobenzoic acid,colorless solid, m.p. 26827l C. (dec.

e. 3-Glutarimido-5-(N-methylcyclopropylcarboxamido)-2,4,6-triiodobenzoic Acid [A; R is cyclopropyl-CON(CH Y is CH CH CH Z isOHlcan be prepared by interacting 3-amino-5-(N-methylcyclopropylcarboxamido)-2,4,6- triiodobenzoic acid withglutaric anhydn'de according to the procedure of Example 1.

f. 3'-Carboxy-5-(N-methylcyclopropylcarboxamido)-2,4,6'-triiodoglutaranilic Acid [B; R is cyclopropyl-CON(CH R and R" are H,Y is CH CH CH Z is OHlcan be prepared by hydrolyzing3-glutarimido-5-(N-methylcyclopropylcarboxamido)-2,4,6-triiodobenzoicacid with dilute sodium hydroxide.

According to the foregoing procedures, cyclohexanecarboxylic acidchloride can be caused to react with 3-amino-5- nitrobenzoic acid andthe resulting 3-cyclohexylcarboxamido- S-nitrobenzoic acidconvertedsuccessively to 3-cyclohexylcarboxamido-S-aminobenzoic acid,3-amino-5-(cyclohexylcarboxamido)-2,4,6-triiodobenzoic acid,3-amino-5-(N- methylcyclohexylcarboxamido)-2,4,6-triiodobenzoic acid, 3-g1utarimido-5-(N-methylcyclohexylcarboxamido)-2,4,6- triiodobenzoic acid[A; R is cyclohexyl CON(CH,-,), Y is CH CH CH, Z is 01-1] and3'-carboxy-5'-(N-methylcyclohexylcarboxamido)-2,4,6-triiodoglutaranilicacid [8; R is cyclohexyl CON(CH,), R and R are H, Y is CH CH Cl-l, X isOH].

EXANIPLE 85 3-Glutarimido-2,4,6-triiodo-N,N-dimethylisophthalamic Acid[A; R is (CHQ NCO, Y is CH CH CH Z is OH], colorless solid, m.p. 275292C., was prepared from 5-amino-2,4,6- triiodo-N,N-dimethylisophthalamicacid and glutaric anhydride according to the method of Example 1, andcan be subsequently hydrolyzed with dilute sodium hydroxide to give 3-carboxy-5 N,N-dirnethylcarbarnoyl )-2 ,4 ,6'-triiodog1utaranilic acid[13; R is (CHQ NCO, R and R" are H, Y is CH CH CHZ is OH].

EXAMPLE 86 a. 3-Amino-2,4,6-triiodo-N,N-diethylbenzamide.

A mixture of 26.6 g. of 3-amino-2,4,6-triiodobenzoyl chloride, 515 ml.of diethylamine and 250 ml. of benzene was stirred at reflux for 20minutes. The reaction mixture was kept at room temperature for 2 days,then filtered and the filtrate concentrated to remove solvent and excessdiethylamine to give 28.7 g. of3-amino-2,4,6-triiodo-N,N-diethylbenzamide as an amber glass. b.N-[3-(N,N-Diethylcarbamoyl)-2,4,6- triiodophenyllsuccinimide [A; R is H,Y is CH CH Z is N(C2HB)]- A mixture of 28.7 g. of3-amino-2,4,6-u'iiodo-N,N-diethylbenzamide and 51.6 g. of succinicanhydride was heated to 1 15 C. Concentrated sulfuric acid (2.5 ml. wasadded, the mixture stirred for 2 to 3 minutes and then poured into300-400 ml. of cold water with stirring. The mixture was treated with300 ml. of percent sodium hydroxide and the solid product collected togive N-[3-(N,N-diethylcarbamoyl)- 2,4,6-triiodophenyl] succinimide, m.p.2l l-2l 8 C.

EXAMPLE 87 a. 3 N,N-Diethylcarbamoyl)-2 ,4 ,6'-triiodosuccinanilic Acidwas prepared by treating a solution of N-[ 3-(N,N- diethylcarbamoyl)-2,4,6-triiodophenyl ]succinirnide in acetone with an excess of 10percent aqueous sodium hydroxide. The solution was stirred for 1 hour atroom temperature, concentrated to remove the solvent and acidified withdilute hydrochloric acid. The product was collected, purified byconversion to its sodium salt and reacidification, and recrystallizedfrom ethyl acetate to give 3'-(N,N-diethylcarbamoyl)-2,4,6-triiod0succinanilic acid, colorless prisms, m.p. 202-205 C. (dec.

b. 3 N,N-Diethylcarbamoyl)-2',4',6-triiodo-N-methylsuccinanilic Acid [B;R is H, R is CH R" is H, Y is CH CH Z is N(CH H ]was prepared bymethylation of 3'-(N,N- diethylcarbamoyl)-2',4',6'-triiodosuccinanilicacid with dimethyl sulfate in potassium hydroxide according to theprocedure of Example 41. The product was obtained as a colorlessamorphous solid both in the free acid and sodium salt forms.

EXAMPLE 88 3'-(N,N-Diethylcarbamoyl)-2',4',6-triiod0-N-ethylsuccinanilicAcid [3; R is H, R is C H R" is H, Y is CH CH Z is N(C H )flwas preparedby alkylation of 3'-( N,N-diethylcarbamoyl)-2,4',6-triiodosuccinanilicacid with diethyl sulfate and potassium hydroxide in acetone solution.The product was obtained in the sodium salt form as a colorlessamorphous solid from methanol-ether.

EXAMPLE 89 a. 3-Amino-2,4,6-triiodo-N,N-dimethylbenzamide.

A mixture of 69.88 g. of 3-amino-2,4,6-triiodobenzoyl chloride and 300ml. of dimethylarnine was stirred for minutes. Sodium hydroxide (50 ml.35 percent) and 50 ml. of water was added, and the reaction mixture wasstirred for 1 hour. The solid product was collected and purified byconversion to its sodium salt form and reconversion to the free acid.The latter was recrystallized from ethanol to give 3-amino-2,4,6-triido-N,N-dimethylbenzamide, pale yellow solid, m.p. l65-167c.

b. 3'-(N,N-Dimethylcarbamoyi)-2',4',6'-triiodoglutaranilic Acid [3; R, Rand R" are H, Y is CH CH CH Z is N(Cl-l;,) ]was prepared by reacting3-amino-2,4,6-triiodo-N,N- dimethylbenzamide with glutaric anhydride,according to the procedure of Example I, and hydrolyzing the resultingN-[3- N,N-dimethylcarbamoyl )-2,4 ,6-triiodophenyl1glutarimide [A; R isH, Y is CH CH CH Z is N(CH,-,) m.p. 312-3] 5 C. The3'-(N,N-dimethylcarba.moyl)-2,4',6'-triiodoglutaranilic acid wasobtained as a colorless solid, m.p. 189l92 C. c.3-(N.N-Dimethylcarbamoyl)-2',4.6-triiodo-N-methylglutaranilic Acid [8; Ris H, R is CH R" is H, Y is CH CH CH Z is N(CH was obtained bymethylation of 3'-(N,N- dimethylcarbamoyl)-2',4',6-l-triiodoglutaranilicacid with dimethyl sulfate according to the procedure of Example 41, andhad the m.p. 205-208 C. when recrystallized from ethyl acetate. Thesodium salt form had the m.p. l9 l-200 C.

The 3 N,N-dimethylcarbamoyl )-2' ,4 ,6-triiodo-N- methylglutaranilicacid by fractional crystallization from acetonitrile could be separatedinto two isomers: lsomer A, light amber crystals, m.p. 201204 C.; sodiumsalt, fine white powder, m.p. 226229 C.; and lsomer B, pale yellowcrystals, m.p. 2l02l3 C.; sodium salt, fine colorless needles, m.p.l942l0 C.; calcium salt, colorless powder.

EXAIVIPLE 90 3 Dimethylcarbamoy] )-2 ,4 ,6-triiodo-N-ethylglutaranilicAcid [8; R is H, R is C l-I R" is H, Y is CH,CH,CH,, Z is N(Cl-l wasprepared by ethylating3'-(dimethylcarbamoyl)-2',4,6'-triiodoglutaranilic acid (Example 89b)with diethyl sulfate according to the procedure of Example 41, and wasobtained in the form of colorless crystals, m.p. ll 82 C. whenrecrystallized from ethyl acetate.

EXAMPLE 9] 3-Glutarimido-2,4,6-triiodobenzamide [A:, R is H, Y is CH CHCh Z is NH A mixture of 100 g. of 3-glutarimido-2,4,6-triiodobenzoicacid and 200 ml. of thionyl chloride was refluxed for minutes. Theexcess thionyl chloride was removed in vacuo and the last traces removedby boiling down with benzene. The residue of acid chloride was treatedwith 200 ml. of concentrated ammonium hydroxide and 200 ml. of water.The reaction mixture was stirred for 2 hours. The solid product wascollected, dried and recrystallized from dimethylformarnide withaddition of a little acetic acid, and then from dioxane to give3glutanirnido-2,4,5-triidodbenzamide, colorless sold, m.p. 268-275 C.

EXAMPLE 92 a. 3-Amino-2,4,6-triiodo-N-methylbenzamide [C; R is H, O isH, Z is NHCH was prepared from the acid chloride of 3-amino-2,4,6-triiodobenzoic acid and aqueous methylamine, and wasobtained in the form of a light yellow powder, m.p. 276278 C. whenrecrystallized from dioxane.

Acetylation of the latter compound provided 3-acetamido-2,4,6-triiodoN-methylbenzamide [C; R is H, O is COCH,,, 2 is NHCH m.p.290292 C. b. 3-Succinirnido-2,4,6-triiodo-N-methylbenzamide [A; R is H,Y is CH CH Z is NHCl-l was prepared from 3-amino-2,4,6triiodo-N-methylbenzamide or 3-acetamido-2,4,6triiodo-N-methylbenzamide and succinic anhydride according to the procedure ofExample 1, and was obtained in the form of colorless crystals, m.p.277284 C. when recrystallized from methanol.

EXAh/IPLE 93 B-glutarimido-2,4,6-triiodo-N-methylbenzamide [A; R is H, Yis CH CH CH Z is NHCH was prepared from 3-amino-2,4,6-triiodo-N-methylbenzamide or 3-acetamido-2,4,6and glutaricanhydride according to the procedure of Example I, and was obtained inthe form of a colorless solid, m.p. 23423 6 C. when recrystallized fromacetic acid.

EXAMPLE 94 a 2,4',6-Triiodo-3'-(methylcarbamoyl)glutaranilic Acid wasprepared by hydrolysis of 3-glutarimido-2,4,6-triiodo-N- methylbenzamide with dilute sodium hydroxide, and was obtained in the form offine colorless needles, m.p. 268270 C. when recrystallized from aceticacid.

b. 2,4,6-Triiodo-3'-methylcarbamoyl)-N-methylglutaranilic Acid [B; R isH, R is CH, R" is H, Y is CH CH Z is NHCH was prepared by methylation of2,4',6'-triiodo- 3'(methylcarbamoyl)glutaranilic acid with dimethylsulfate according to the procedure of Example 41, and was obtained inthe form of a colorless solid, m.p. l64168 C. when recrystallized fromethyl acetate; sodium salt, m.p. 255256 C. (decompan.

EXAMPLE 95 2,4,6-triiodo-3-(methylcarbamoyl)succinanilic Acid wasprepared by hydrolysis of 3-succinimido-2,4,6-triiodo-N- methylbenzamide(Example 92b) with dilute sodium hydroxide, and was obtained as acolorless solid, m.p. 246-249 C. The latter can be N-methylated withdimethyl sulfate to produce2,4,6-triiodo-3"(methylcarbamoyl)-N-methylsuccinanilic acid [8; R is H,R is CH R" is H, Yis CH CH Z is NHCH EXAMPLE 96 EXAMPLE 97 3'-Carbomethoxy-2 ,4 ,6-triiodo-N-ethy1succinanilic Acid [8; R is H, R isCH CH R is H, Y is CH CH Z is OCH was prepared by ethylation of3-carbomethoxy-2',4,6- triiodosuccinanilic acid with diethyl sulfate,and was obtained in the form ofits sodium salt as a colorless amorphoussolid.

EXAMPLE 98 a. 3-Carbethoxy-2,4,6-triiodoglutaranilic Acid was preparedfrom ethyl 3-amino-2,4,-triiodobenzoate and glutaric anhydride, followedby mild alkaline hydrolysis of the resulting ethyl3-glutarimido-2,4,6-triiodobenzoate [A; R is H, Y is CH CH CH Z is OC Hand was obtained as a colorless solid, m.p. 159-l 6 1 C. b.3-Carbethoxy-2',4,6'-triiodo-N-methylglutaranilic Acid [B; R is H, R isCH R is H, Y is CH CH CH Z is OC H can be prepared by methylation of3-carbethoxy-2,4,6'- triiodoglutaranilic acid with dimethyl sulfate.

3,5-Diacetyl-2,4,6-triiodoaniline [C; R is CH CO, Q is H, Z is CH or3,5-dibenzoyl-2,4,6-triiodoaniline [C; R is C H CO, Q is H, Z is C H(prepared by interacting the diacid chloride of3-amino-2,4,6-triiodoisophthalic acid with methyllithium orphenyllithium, respectively) can be caused to react with glutaricanhydride according to the procedure of Example 1 to give, respectively,N-(3,5-d iacetyl-2,4,6- triiodophenyl)glutarimide [A; R is CH CO, Y isCH CH CH,, Z is CH or N-(3,5-dibenzoyl-2,4,6-triiodophenyl)glutarimide[A; R is C H CO, Y is CH CH Ch Z is C H which in turn can be hydrolyzedwith dilute sodium hydroxide to give, respectively,3,5-diacetyl-2,4,6-triiodogluta.ranilic acid [3; R is CH CO, R and R"are H, Y is CH CH CH Z is CH or 3,52,4,6-triiodoglutaranilic acid [8; Ris C H CO, R and R are H, Y is CH CH CH Z is C H EXAMPLE 99 a.5-Glutarimido-2,4,6-triiodoisophthalamide [A; R is N H CO, Y is CH CH CHZ is Nl-l can be prepared from 5- amino-Z,4,6-triiodoisophthalamide(m.p. 305 C., decompn., prepared from 5-amino-2,4,6-triiodoisophthalicacid by treatment with thionyl chloride and then ammonium hydroxide) andglutaric anhydride.

b. 3,5'-Dicarbamoyl-2,4,o triiodoglutaranilic Acid [8; R is H NCO, R andR" are H, Y is CH CH CH Z is NH can be prepared by mild alkalinehydrolysis of 5-glutarimido-2,4,6- triiodoisophthalamide.

EXAMPLE 100 a. S-Glutarimido-Z,4,6-triiodo-N,N-dimethylisophthalamide[A; R is CH NHCO, Y is CH CH,CH Z is NHCH was prepared from5-amino-2',4,6-triiodoN,N'- dimethylisophthalamide (Example 82a) andglutaric anhydride, and was obtained in the form of colorless flakes,m.p. 304-3l4 C.

b. 2,4',6-Triiodo-3,5-bis(methylcarbamoyl)glutaranilic Acid [3; R is CHNHCO, R and R" are H, Y is CH,CH,CH Z is N'HCHlils colorless powder,m.p. 267-27lC. (decompn.), was prepared by mild alkaline hydrolysis of5- glutarimido-Z.4,6-triiodo-N .N -di'methylisophthalamide.

EXAMPLE 101 3 ,5 -bis( Dimethylcarbamoyl )-2,4,6'-N-methyltriiodooxalanilic Acid [3; R is (CH NCO, R is CH R" is H,Y is single bond, Z is N(CH;i)zl- (is-isomer. Colorless needles. m.p.306-3l0 C.; and trans-isomer. colorless needles. m.p. 253-260 C., wereprepared by methylation (dimethyl sulfate) of lsomers A and B,respectively, of 3,5- bis(dimethylcarbamoyl)-2',4,6-triiodooxa.lanilicacid (Example EXAMPLE 102 a.5-Maleimido-2,4,6-triiodo-N,N,N,N-tetramethylisophthalamide [A; R is(CH:t)2NCO. Y is CH=CH, Z is N(CH,-,)2], sis-isomer, colorless needles,m.p. above 360 C.; and trans-isomer, yellow crystals, m.p. above 360 C.,were prepared from 5-amino-2,4,6.-triiodo-N ,N,N,N'-tetramethylisophthalamide and maleic anhydride. 77

b. 3,5-bis(Dimethylcarbamoyl)-2,4,6-triiodomaleanilic Acid [[3, R is (CHhN CO, Rand R are H, Y is CH=CH, Z is N(CH:i)2], cis-isomer, colorlessneedles, m.p. 262-265 C.; and trans-isomer, colorless plates, m.p. 267-27l C., were prepared by mild alkaline hydrolysis of the cisandtrqns-ismoers, respectively, of 5 maleimido-2,4,6-triid0-N,N,N,N-tetramethylisophthalamide.

EXAMPLE 103 a. 3-Glutarimido-2,4,6-triiodo-N-ethylbenzamide [A; R is H,Y is CH CH CH Z is NHC H colorless powder, m.p. 227-229 C., was preparedfrom 3-amino-2,4,6-triiodo-N- ethylbenzamide (prepared from the acidchloride of 3-amino- 2,4,6-triiodobenzoic acid and aqueous ethylamine)and glutaric anhydride. b. 3-(Ethylcarbamoyl)-2,4,6'-triiodoglutaranilicAcid [8; R, R and R are H, Y is CHzCHzCHzz, Z is NHCZH colorlessneedles, m.p. 262265 C., was prepared by mild alkaline hydrolysis of3-glutarimido-Z,4,6-triiodo-N-ethylbenzamide. c. 3-(Ethylcarbamoyl)-2',4,6-triiodo-N-methylglutaranilic Acid [8; R is H, R is CH3, R is H,Y is CH2CHzCH2,Z is NHC2H5], colorless powder, m.p. 226235 C., wasprepared by methylation (dimethyl sulfate) of3-(ethylcarbamoyl)-2,4',6'-triiodoglutaranilic acid.

EXAMPLE 104 a. 3-(Dimethylcarbamoyl)-2,4',6-triiodooxalanilic Acid [B;R, R and R are H, Y is single bond, 2 is N(CH colorless powder, m.p.l53l58- C. (decompn.), was prepared from 3-amino-Z,4,-triiodo-N,N-dimethylbenzarnide (Example 89a) and ethyl oxalylchloride, followed by alkaline hydrolysis of the resulting ethyl ester.

b. 3-(Dimethylcarbamoyl)-2,4,6'-triiodo-N-methyloxanilic Acid [8; R isH, R is CH R is H, Y is single bond, Z is N(CH colorless crystals, m.p.l79-l81 C. (decompn.), was prepared by methylation (dimethyl sulfate) of3- (dimethylcarbamoyl)-2,4,6-triiodooxalanilic acid.

EXAMPLE 105 a. 3Succinimido-2,4,6-triiodo-N,N-dimethylbenzamide [A; R isH, Y is CH CH Z is N(CH colorless crystals, m.p. 263266C., was preparedfrom 3-amino-2,4,6-triiodo-N,N- dimethylbenzamide (Example 89a) andsuccinic anhydride.

b. 3-(Dimethylcarbamoyl)-Z'.4.6-triiodosuccinanilic Acid [B1 R, R and R"are H. Y is CH- CH ,Z is NlCHsh], Colorless prisms, m.p. l66-l70 C., wasprepared by mild alkaline hydrolysis of3-succinimido-2,4,6-triiodo-N,N-dimethylbanamide.

c. 3'-(Dimethylcar bamoyl)-2,4,6 triiodo-N-methylsuccinanilic Acid [B; Ris H, R is q g gg, Y is CH2CH2, Z is N(CH Isomer A. colorless solid,m.p. 186l90 C.: and Isomer B. colorless powder. m.p. l88220 C..wasprepared by methylation (dimethyl sulfate) of3'-(dimethylcarbamoyl)-2.4.6-triiodosuccinanilic acid.

EXAMPLE 106 a. 3-Glutarimido-2,4,6-triiodo-N.N-diethylbenzamide [A; R isH. Y is CHQCH CH Z is N(C2H.-.)2], colorless prisms, m.p. 23623 9 C.,was prepared from 3-amino-2,4,6-triiodo- N,N-diethylbenzamide (Example86a) and glutaric anhydride. b.3-lDiethylcarbamoyl)2'.4.6-triiodoglutaranilic Acid [B: R. R and R" areH, Y is CH CH2CH ,Z is N(C2H5)zi, colorless prisms. m.p. 207-21l C., wasprepared by mild alkaline hydrolysis of3-glutarimido-2.4.6-triiodo-N.N-diethylbenzamide. I

c. 3-(Diethylcarbamoyl)-2.4,6'-triiodo-N-methylglutaranilic Acid [B: Ris H, R is CH R is H, Y is CH CH1CH Z is N(C1H.=)g]. colorless powder.m.p. l87-l89 C., was prepared by methylation (dimethyl sulfate) of3-(diethylcarbamoyl)2,4.6-triiodoglutaranilic acid.

EXAMPLE 107 a. 4-[2,4,6-Triiodo-3-(succinimido)benzoyl]morpholine [A: Ris H. Y is CHgCHg, Z is NiCHz)40]. colorless needles. m.p. l80-l87 C.,was prepared by reacting 2.4,6-tiiiodo- 3-succinimidobenzoic acid(Example 13) with thionyl chlo ride and then with aqueous morpholine.

b. 2',4,6-Triiodo-3-(morpholinocarbonyl)succinanilic Acid [B: R. R and Rare H, Y is CH CH ,Z is N(CH- ).O], colorless cubes. m.p. 246249 C.. wasprepared by mild alkaline hydrolysis of4-[2,4,6-triiodo-3-(succinimido)benzoyl]- morpholine.

c. 2.4.6-Triiodo-3(morpholinocarbonyl)-N-methylsuccinanilic Acid [B: Ris H, R is CH;;, R is H, Y is CHQCHLH Z is N(CH2)4O] can be prepared bymethylation (dimethyl sulfate) of 2 ,4' ,6-triiodo3'-(morpholinocarbonyl)-succinanilic acid.

EXAMPLE I08 I c. 2' ,4 ,6-Triiodo-3-(morpholinocarbonyll-N-methylglutaranilic Acid [8; R is H, R is CH R"is H, Y is CH,CH CH Z is N(CH O] was prepared by methylation (dimethylsulfate) of 2,4,6'-triiodo-3'-(morpholinocarbonyl)glutaranilic acid, andobtained as a mixture of isomers, m.p. l86l90 C., which could beseparated into two isomers, lsomer A, colorless powder, m.p. l9l-l94 C.,and lsomer B, colorless needles, m.p. l74l83 C., sodium salt, colorlesspowder, m.p. l97207 C.

EXAMPLE 109 a. 3,5-Di(succinirnido)-2,4,6-triiodo-N,N-dimethylbenzamide[A; R is succinirnido, Y is CH CH Z is N(CH yellow prisms, m.p. above330 C., was prepared by reacting 3,5-di(succinimido)-2,4,6-triiodobenzoic acid (Example 76) with with thionylchloride and then with aqueous dimethylamine. b.N,N-[S-(Dimethylcarbamoyl)-2,4,6-triiodo-m-phenylenelbis-[succinamicacid] (B; R is HOOC(CH ),CONH, R and R" are H, Y is CH CH Z is N(CH 1,colorless crystals, m.p. 228230 C. (decompn.), was prepared by mildalkaline hy lrolysis of 3.5 di (succinimido) 2,4,6 triiodo-N,N-dimethylbenzamide.

EXAMPLE 1 1O 3-{3-[(2-Carboxyethyl)sulfonyllpropionamido}-2.4.6-triiodo-5-(N-methylacetamido)benzoic Acid [8; R is CH3CON (CH3). R and R are H.Y is CHgCH-gSOgCHgCHg, Z is OH].

To a solution of 29.54 g. of 3-[3-(2-carboxyethylthio)- propionamido-2,4,6-triiodo-5-( N-methylacetamido )benzoic acid (Example 56) in 175ml. of glacial acetic acid at room temperature was added in portions8.69 g. of an aqueous solution containing 2.695 g. of hydrogen peroxide.The mixture was heated on a steam beam for 1 hour, and then concentratedin vacuo to remove the solvents. The residue was dissolved in aqueoussodium hydroxide, decolorized with activated charcoal and reprecipitatedwith hydrochloric acid. The product was collected and dried to givel7.75 g. of 3-{3- [(Z-carboxyethyl)sulfony|]propionamido}-2, 4,6-triiodo-5- solid, mp. 234-24l C. (decompn.

EXAMPLE 1 l l a. 2,4,6-Triiodo-3-{ 3 [2-(methoxycarbonyl)ethylthiolpropionamido}-5-(N-ethylacetamidolbenzoic Acid (B; R is CH;CON(C1H.=). Ris H. R" is CH3. Y is CH2CH2SCH2CH-g, Z is OH], colorless powder, m.p.l52l70 C., was prepared from3-amino-5-(N-ethylacetamido)-2,4,6-triiodobenzoic acid and ClCOCH,CH SCHCH COOCH according to the procedure of Example 55.

b. 3-[ 3-( Z-Carboxyethylthio )propionarnido]-2,4,6-triiodo-5-(N-ethylacetamido)benzoic Acid [3; R is CH CON(C H R and R" are H, Y isCH CH SCH CH Z is OH], colorless powder, m.p. l-l99 C was prepared byalkaline hydrolysis of 2,4,6-triiodo-3-{3-[2-(methoxycarbonyllethylthio]propionamido}-5-(N-ethylacet-amido)benzoic acid according to theprocedure of Example 56.

c. 3- 3-( Z-Carboxyethylsulfon yl )propi0namido]-2,4,6-triiodo-5-(N-ethylacetamido)benzoic Acid [B; R is CH OON(C2H5), R and R"are H, Y is CH2cHJ )H2(:H2, Z is OH] can be prepared by treating3-[3-(2-carboxyethylthio)propionamido ]-2,4,6-triiodo-5-( N-ethylacetamido)benzoic acid with hydrogen peroxide by the proceduredescribed in Example I l0.

EXAMPLE l 12 a. 2,4,6-Triiodo-S-maleimidoisophthalic Acid [A; R is HOOC,Y is CH CH, 2 is OH], tan prisms, m.p. above 328 C. (decompn. wasprepared from 5-amino-2,4,6- triiodoisophthalic acid and maleicanhydride.

b. 2',4,6'-Triiodo-3',5'-dicarboxymaleanilic Acid [8; R is HOOC, R andR" are H, Y is CH CH, Z is OH] can be prepared by mild acid hydrolysisof 2,4,6-triiodo-5- 3-Amino 2 ,4,6-triiodo-5-( N-methylacetamido )-N,N-

dimethylbenzamide, according to claim 1 wherein R is N- methylacetamidoand Z is dimethylamino.

methyl-acetamido an 4-[ 3-Amino- 2,4,6-triiodo-5-( N-methylacetamido 5benzoyl ]morpholine,

according to Claim 1 wherein R is N- d 2 is morpholino.

2. 3-Amino-2,4,6-triiodo-5-(N-methylacetamido)-N,N-dimethylbenzamide,according to claim 1 wherein R is N-methylacetamido and Z isdimethylamino. 3.4-(3-Amino-2,4,6-triiodo-5-(N-methylacetamido)-benzoyl)morpholine,according to Claim 1 wherein R is N-methyl-acetamido and Z ismorpholino.